HIV inhibiting pyrimidine derivatives

ABSTRACT

This invention concerns the use of the compounds of formula  
                 
 
the N-oxides, the pharmaceutically acceptable addition salts and the stereochemically isomeric forms thereof, wherein A is CH, CR 4  or N; n is 0 to 4; Q is hydrogen or —NR 1 R 2 ; R 1  and R 2  are selected from hydrogen, hydroxy, C 1-12 alkyl, C 1-12 alkyloxy, C 1-12 alkylcarbonyl, C 1-12 alkyloxycarbonyl, aryl, amino, mono- or di(C 1-12 alkyl)-amino, mono- or di(C 1-12 alkyl)aminocarbonyl wherein each C 1-12 alkyl may optionally be substituted; or R 1  and R 2  taken together may form pyrrolidinyl, piperidinyl, morpholinyl, azido or mono- or di(C 1-12 alkyl)aminoC 1-4 alkylidene; R 3  is hydrogen, aryl. C 1-6 alkylcarbonyl, optionally substituted C 1-6 alkyl, C 1-6 alkyloxy-carbonyl; and R 4  is hydroxy, halo, optionally substituted C 1-6 alkyl, C 1-6 alkyloxy, cyano, aminocarbonyl, nitro, amino, trihalomethyl, trihalomethyloxy; R 5  is hydrogen or C 1-4 alkyl; L is optionally substituted C 1-10 alkyl, C 3-10 alkenyl, C 3-10 alkynyl, C 3-7 cycloalkyl; or L is —X 1 —R 6  or —X 2 -Alk-R 7  wherein R 6  and R 7  are optionally substituted phenyl; X 1  and X 2  are —NR 3 —, —NH—NH—, —N═N—, —O—, —S—, —S(═O)— or —S(═O) 2 —; Alk is C 1-4 alkanediyl; aryl is potionally substituted phenyl; Het is an optionally substituted aliphatic or aromatic heterocyclic radical; for the manufacture of a medicine for the treatment of subjects suffering from HIV (Human Immunodeficiency Virus) infection. It further relates to new compounds being a subgroup of the compounds of formula (I), their preparation and compositions comprising them.

The present invention is concerned with pyrimidine derivatives havingHIV replication inhibiting properties. The invention further relates tomethods for their preparation and pharmaceutical compositions comprisingthem. The invention also relates to the use of said compounds in themanufacture of a medicament useful for the treatment of subjectssuffering from HIV (Human Immunodeficiency Virus) infection.

Compounds structurally related to the present compounds are disclosed inthe prior art.

JP-2,052,360, JP-2,308,248, JP-9,080,676 and JP-9,068,784 disclose anumber of trisubstituted pyrimidines useful in photographic material.JP-8,199,163 discloses trisubstituted pyrimidines useful in an organicelectroluminescent device. JP-2,300,264 and GB-1,477,349 disclosepyrimidinetriamines for their use in the dye industry.

J. Indian Chem. Soc. (1975), 52(8), 774-775 discloses the synthesis ofsome bis(arylamino)pyrimidines. J. Heterocycl. Chem. (1973), 10(2),167-171 discloses the condensation of various aminopyrimidines withpicryl halides. J. Org. Chem. (1961), 26, 4433-4440 discloses severaltriaminopyrimidines as intermediates in the synthesis oftriazolo[4.5-d]pyrimidines.

WO 91/18887 discloses diaminopyrimidines as gastric acid secretioninhibitors.

Unexpectedly, it has now been found that the compounds of formula (I)effectively inhibit the replication of the Human Immunodeficiency Virus(HIV) and consequently may be useful for the treatment of individualsinfected by HIV.

The present invention concerns the use of the compounds of formula

the N-oxides, the pharmaceutically acceptable addition salts and thestereochemically isomeric forms thereof, wherein

-   -   A is CH, CR⁴ or N;    -   n is 0, 1, 2, 3 or 4;    -   Q is hydrogen or —NR¹R²;    -   R¹ and R² are each independently selected from hydrogen,        hydroxy, C₁₋₁₂alkyl, C₁₋₁₂alkyloxy, C₁₋₁₂alkylcarbonyl,        C₁₋₁₂alkyloxycarbonyl, aryl, amino, mono- or        di(C₁₋₁₂alkyl)amino, mono- or di(C₁₋₁₂alkyl)aminocarbonyl        wherein each of the aforementioned C₁₋₁₂alkyl groups may        optionally and each individually be substituted with one or two        substituents each independently selected from hydroxy,        C₁₋₆alkyloxy, hydroxyC₁₋₆alkyloxy, carboxyl,        C₁₋₆alkyloxycarbonyl, cyano, amino, imino, aminocarbonyl,        aminocarbonylamino, mono- or di(C₁₋₆alkyl)amino, aryl and Het;        or    -   R¹ and R² taken together may form pyrrolidinyl, piperidinyl,        morpholinyl, azido or mono- or        di(C₁₋₁₂alkyl)aminoC₁₋₄alkylidene:    -   R³ is hydrogen, aryl, C₁₋₆alkylcarbonyl, C₁₋₆alkyl,        C₁₋₆alkyloxycarbonyl, C₁₋₆alkyl substituted with        C₁₋₆alkyloxycarbonyl; and    -   each R⁴ independently is hydroxy, halo, C₁₋₆alkyl, C₁₋₆alkyloxy,        cyano, amino-carbonyl, nitro, amino, trihalomethyl,        trihalomethyloxy or C₁₋₆alkyl substituted with cyano or        aminocarbonyl:    -   R⁵ is hydrogen or C₁₋₄alkyl;    -   L is C₁₋₁₀alkyl, C₃₋₁₀alkenyl, C₃₋₁₀alkynyl, C₃₋₇cycloalkyl, or        C₁₋₁₀alkyl substituted with one or two substituents        independently selected from C₃₋₇cycloalkyl, indanyl, indolyl and        phenyl, wherein said phenyl, indanyl and indolyl may be        substituted with one, two, three, four or where possible five        substituents each independently selected from halo, hydroxy,        C₁₋₆alkyl. C₁₋₆alkyloxy, cyano, aminocarbonyl,        C₁₋₆alkyloxycarbonyl, formyl, nitro, amino, trihalomethyl,        trihalomethyloxy and C₁₋₆alkylcarbonyl; or L is —X¹—R⁶ or        —X²-Alk-R⁷ wherein        -   R⁶ and R⁷ each independently are phenyl or phenyl            substituted with one, two, three, four or five substituents            each independently selected from halo, hydroxy, C₁₋₆alkyl,            C₁₋₆alkyloxy. C₁₋₆alkylcarbonyl, C₁₋₆alkyloxycarbonyl,            formyl, cyano, aminocarbonyl, nitro, amino, trihalomethyloxy            and trihalomethyl; and        -   X¹ and X² are each independently —NR³—, —NH—NH—, —N═N—, —O—,            —S—, —S(═O)— or —S(═O)₂—;        -   Alk is C₁₋₄alkanediyl;    -   aryl is phenyl or phenyl substituted with one, two, three, four        or five substituents each independently selected from halo,        C₁₋₆alkyl, C₁₋₆alkyloxy, cyano, nitro and trifluoromethyl;    -   Het is an aliphatic or aromatic heterocyclic radical; said        aliphatic heterocyclic radical is selected from pyrrolidinyl,        piperidinyl, homopiperidinyl, piperazinyl, morpholinyl,        tetrahydrofuranyl and tetrahydrothienyl wherein each of said        aliphatic heterocyclic radical may optionally be substituted        with an oxo group; and said aromatic hetero-cyclic radical is        selected from pyrrolyl, furanyl, thienyl, pyridyl, pyrimidinyl,        pyrazinyl and pyridazinyl wherein each of said aromatic        heterocyclic radical may optionally be substituted with hydroxy;    -   for the manufacture of a medicine for the treatment of subjects        suffering from HIV (Human Immunodeficiency Virus) infection.

The present invention also relates to a method of treating warm-bloodedanimals suffering from HIV (Human Immunodeficiency Virus) infection.Said method comprises the administration of a therapeutically effectiveamount of a compound of formula (I) or any subgroup thereof, a N-oxideform, a pharmaceutically acceptable addition salt or a stereochemicallyisomeric form thereof in admixture with a pharmaceutical carrier.

This invention also concerns compounds of formula

the N-oxides, the pharmaceutically acceptable addition salts and thestereochemically isomeric forms thereof, wherein L, Q, R³, R⁴, R⁵ and Aare as defined under formula (I), and

-   -   R^(4′) is halo, C₁₋₆alkyl, cyano, aminocarbonyl, nitro,        trihalomethyl, trihalomethyloxy or C₁₋₆alkyl substituted with        cyano or aminocarbonyl;    -   n′ is 0, 1, 2 or 3;    -   with the proviso that Q and L are other than anilino.        2,4,6-trinitro-anilino, 3-methoxy-anilino, 4-methoxy-anilino,        3,4-dimethoxy-anilino, 3-chloro-4-fluoro-anilino,        4-cyano-anilino, 2-(C₁₋₆alkyl)-anilino, 4-(C₁₋₆alkyl)-anilino,        3-chloro-anilino, 4-bromo-anilino, 4-nitro-anilino and        4-chloro-anilino.

As used in the foregoing definitions and hereinafter halo definesfluoro, chloro, bromo and iodo: C₁₋₄alkyl as a group or pant of a groupencompasses the straight and branched chained saturated hydrocarbonradicals having from 1 to 4 carbon atoms such as, for example, methyl,ethyl, propyl, butyl and the like. C₁₋₆alkyl as a group or part of agroup encompasses the straight and branched chained saturatedhydrocarbon radicals as defined in C₁₋₄alkyl as well as the higherhomologues thereof containing 5 or 6 carbon atoms such as, for examplepentyl or hexyl; C₁₋₁₀alkyl as a group or part of a group groupencompasses the straight and branched chained saturated hydrocarbonradicals as defined in C₁₋₆alkyl as well as the higher homologuesthereof containing 7 to 10 carbon atoms such as, for example, heptyl,octyl, nonyl or decyl; C₁₋₁₂alkyl as a group or part of a groupencompasses the straight and branched chained saturated hydrocarbonradicals as defined in C₁₋₁₀alkyl as well as the higher homologuesthereof containing 11 or 12 carbon atoms such as, for example, undecyl,dodecyl and the like; C₁₋₄alkylidene as a group or part of a groupdefines bivalent straight and branched chained hydrocarbons having from1 to 4 carbon atoms such as, for example, methylene, ethylidene,propylidene, butylidene and the like; C₁₋₄alkanediyl as a group or partof a group encompasses those radicals defined under C₁₋₄alkylidene aswell as other bivalent straight and branched chained hydrocarbons havingfrom 1 to 4 carbon atoms such as, for example, 1,2-ethanediyl,1,3-propanediyl, 1,4-butanediyl and the like: C₃₋₇cycloalkyl as a groupor part of a group is generic to cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl and cycloheptyl; C₃₋₁₀alkenyl as a group or part of a groupdefines straight and branch chained hydrocarbon radicals containing onedouble bond and having from 3 to 10 carbon atoms such as, for example,2-propenyl, 2-butenyl, 2-pentenyl, 3-pentenyl, 3-methyl-2-butenyl,3-hexenyl, 3-heptenyl, 2-octenyl, 2-nonenyl, 2-decenyl and the like,whereby the carbon atom attached to the pyrimidine ring is preferably analiphatic carbon atom: C₃₋₁₀alkynyl as a group or part of a groupdefines straight and branch chained hydrocarbon radicals containing onetriple bond and having from 3 to 10 carbon atoms such as, for example,2-propynyl, 2-butynyl, 2-pentynyl, 3-pentynyl, 3-methyl-2-butynyl,3-hexynyl, 3-heptynyl, 2-octynyl, 2-nonynyl, 2-decynyl and the like,whereby the carbon atom attached to the pyrimidine ring is preferably analiphatic carbon atom.

It is to be understood that the three substituents [L, Q andNR³(optionally substituted phenyl or pyridyl)] on the pyrimidine ringcan be on any free position of the pyrimidine ring. Thus, given thefollowing numbering of the pyrimidine ring

the three substituents may be connected to the pyrimidine ring in threedifferent ways:

-   -   2-L, 4-Q, 6-NR³(optionally substituted phenyl or pyridyl); or    -   4-L, 2-Q, 6-NR³(optionally substituted phenyl or pyridyl); or    -   6-L, 4-Q, 2-NR³(optionally substituted phenyl or pyridyl).

The positions 4 and 6 are equivalent to one another. For instance,substitution pattern 6-L, 4-Q, 2-NR³(optionally substituted phenyl orpyridyl), which is a preferred substitution pattern, is equivalent tosubstitution pattern 4-L, 6-Q, 2-NR³(optionally substituted phenyl orpyridyl). Said subgroup of compounds is represented by formula

An interesting group of compounds are the compounds of formula

Of particular interest are those compounds of formula (I′-1) wherein Land Q are other than anilino, 2,4,6-trinitro-anilino,4-(C₁₋₆alkyl)-anilino. 4-bromo-anilino, 4-nitro-anilino and4-chloro-anilino: and of more particular interest are those compounds offormula (I′-1) wherein R^(4′) is cyano, aminocarbonyl or C₁₋₆alkylsubstituted with cyano or aminocarbonyl.

The addition salts as mentioned herein are meant to comprise thetherapeutically active addition salt forms which the compounds of thepresent invention are able to form with appropriate acids, such as, forexample, inorganic acids such as hydrohalic acids, e.g. hydrochloric orhydrobromic acid; sulfuric; nitric; phosphoric and the like acids; ororganic acids such as, for example, acetic, propanoic, hydroxyacetic,lactic, pyruvic, oxalic, malonic, succinic, maleic, fumaric, malic,tartaric, citric, methanesulfonic, ethanesulfonic, benzenesulfonic,p-toluenesulfonic, cyclamic, salicylic, p-amino-salicylic, pamoic andthe like acids.

The pharmaceutically acceptable addition salts as mentioned hereinaboveare also meant to comprise the therapeutically active non-toxic base, inparticular, a metal or amine addition salt forms which the compounds ofthe present invention are able to form. Said salts can conveniently beobtained by treating the compounds of the present invention containingacidic hydrogen atoms with appropriate organic and inorganic bases suchas, for example, the ammonium salts, the alkali and earth alkaline metalsalts, e.g. the lithium, sodium, potassium, magnesium, calcium salts andthe like, salts with organic bases. e.g. the benzathine,N-methyl-D-glucamine, hydrabamine salts, and salts with amino acids suchas, for example, arginine, lysine and the like. Conversely said saltforms can be converted by treatment with an appropriate base or acidinto the free acid or base form.

The term addition salts also comprises the hydrates and the solventaddition forms which the compounds of the present invention are able toform. Examples of such forms are e.g. hydrates, alcoholates and thelike.

The term stereochemically isomeric forms of compounds of the presentinvention, as used hereinbefore, defines all possible compounds made upof the same atoms bonded by the same sequence of bonds but havingdifferent three-dimensional structures which are not interchangeable,which the compounds of the present invention may possess. Unlessotherwise mentioned or indicated, the chemical designation of a compoundencompasses the mixture of all possible stereochemically isomeric formswhich said compound may possess. Said mixture may contain alldiastereomers and/or enantiomers of the basic molecular structure ofsaid compound. All stereochemically isomeric forms of the compounds ofthe present invention both in pure form or in admixture with each otherare intended to be embraced within the scope of the present invention.

Some of the compounds of the present invention may also exist in theirtautomeric forms. Such forms although not explicitly indicated in theabove formula are intended to be included within the scope of thepresent invention.

Whenever used hereinafter, the term “compounds of the present invention”is meant to include the compounds of formula (I), (I-1), (I′), (I′-1) orany subgroup thereof, also the N-oxides, the pharmaceutically acceptableaddition salts and all stereoisomeric forms.

The group containing those compounds of the present invention wherein Qis NR¹R², each R⁴ independently is hydroxy, halo, C₁₋₆alkyl,C₁₋₆alkyloxy, cyano, amino-carbonyl, nitro, amino, trihalomethyl ortrihalomethyloxy; L is C₁₋₁₀alkyl, C₃₋₁₀alkenyl, C₃₋₁₀alkynyl,C₃₋₇cycloalkyl, or C₁₋₁₀alkyl substituted with one or two substituentsindependently selected from C₃₋₇cycloalkyl, indolyl or indolylsubstituted with one, two, three or four substituents each independentlyselected from halo, C₁₋₆alkyl, C₁₋₆alkyloxy, cyano, aminocarbonyl,nitro, amino, trihalomethyl, trihalomethyloxy and C₁₋₆alkylcarbonyl,phenyl or phenyl substituted with one, two, three, four or fivesubstituents each independently selected from halo, hydroxy, C₁₋₆alkyl,C₁₋₆alkyloxy, cyano, aminocarbonyl, nitro, amino, trihalomethyl,trihalomethyloxy and C₁₋₆alkyl-carbonyl; or L is —X¹—R⁶ wherein R⁶ isphenyl or phenyl substituted with one, two, three, four or fivesubstituents each independently selected from halo, C₁₋₆alkyl,C₁₋₆alkyloxy, C₁₋₆alkylcarbonyl, cyano, nitro and trifluoromethyl; is ofinterest.

Also of interest is the group containing those compounds of the presentinvention wherein Q is NR¹R²; each R⁴ independently is hydroxy, halo,C₁₋₆alkyl, C₁₋₆alkyloxy, cyano, aminocarbonyl, nitro, amino,trihalomethyl or trihalomethyloxy; L is C₁₋₁₀alkyl substituted with oneor two substituents independently selected from phenyl or phenylsubstituted with one, two, three, four or five substituents eachindependently selected from halo, hydroxy, C₁₋₆alkyl, C₁₋₆alkyloxy,cyano, aminocarbonyl, nitro, amino, trihalomethyl, trihalomethyloxy andC₁₋₆alkylcarbonyl; or L is —X¹—R⁶ wherein R⁶ is phenyl or phenylsubstituted with one, two, three, four or five substituents eachindependently selected from halo, C₁₋₆alkyl, C₁₋₆alkyloxy,C₁₋₆alkylcarbonyl, cyano, nitro and trifluoromethyl; with the provisothat compounds

-   (a) N2-hydroxy-N2-methyl-N4,N6-diphenyl-2,4,6-pyrimidinetriamine;-   (b)    N,N,N′,N′,N″,N″-hexakis(3-methylphenyl)-2,4,6-pyrimidinetriamine;-   (c)    N4-methyl-N2-(2-methylphenyl)-N4-phenyl-2,4,6-pyrimidinetriamine;-   (d)    N4-methyl-N2-(2-methylphenyl)-N4-phenyl-6-(phenylmethyl)-2,4-pyrimidine    diamine;-   (e) N4-(2-methylphenyl)-6-(phenylmethyl)-2,4-pyrimidinediamine;-   (f) N,N′,N″-tris(4-methoxyphenyl)-2,4,6-pyrimidinetriamine;-   (g)    N,N-bis(4-hexylphenyl)-6-(4-methoxyphenoxy)-2,4-pyrimidinediamine;-   (h)    N2,N4-bis(4-hexylphenyl)-N6,N6-dimethyl-2,4,6-pyrimidinetriamine:-   (i) N,N′,N″-tris(4-hexylphenyl)-2,4,6-pyrimidinetriamine.-   (j)    N2,N2-dimethyl-N4,N6-bis(4-methylphenyl)-2,4,6-pyrimidinetriamine:-   (k) N,N′,N″-tris(4-methylphenyl)-2,4,6-pyrimidinetriamine:-   (l) N,N′,N″-triphenyl-2,4,6-pyrimidinetriamine;-   (m) N,N,N′N′,N″,N″-hexakis(4-ethoxyphenyl)-2,4,6-pyrimidinetriamine:-   (n) N4,N6-bis(2-chlorophenyl)-2,4,6-pyrimidinetriamine:-   (o) N4,N6-bis(3-chlorophenyl)-2,4,6-pyrimidinetriamine;-   (p) N4,N6-bis(2-ethoxyphenyl)-2,4,6-pyrimidinetriamine:-   (q) N4,N6-bis(4-ethoxyphenyl)-2,4,6-pyrimidinetriamine;-   (r) N4,N6-bis(2-methylphenyl)-2,4,6-pyrimidinetriamine;-   (s) N4,N6-bis(4-bromophenyl)-2,4,6-pyrimidinetriamine;-   (t) N4,N6-bis(4-methylphenyl)-2,4,6-pyrimidinetriamine:-   (u) N2,N4-bis(4-methoxyphenyl)-2,4,6-pyrimidinetriamine:-   (v) N2,N4-bis(4-methylphenyl)-2,4,6-pyrimidinetriamine;-   (w) N,N′,N″-tris(2,4,6-trinitrophenyl)-2,4,6-pyrimidinetriamine;-   (x) N4,N6-bis(4-chlorophenyl)-2,4,6-pyrimidinetriamine:-   (y) N4.N6-bis(4-methoxyphenyl)-2,4,6-pyrimidinetriamine,-   (z) N2,N4,N6-trimethyl-N2,N4,N6-triphenyl    pyrimidine-2,4,6-triyltriamine;-   (aa) N4,N4-dimethyl-N2,N6-di-p-tolyl-pyrimidine-2,4,6-triyltriamine;    and-   (bb) N2,N4-diphenyl-pyrimidine-2,4,6-triyltriamine are not included.

Suitably, Q may also be hydrogen in the above two groups of interest.

A special group of compounds are those compounds of formula (I) or (I′)wherein n is at least 1 and at least one R⁴ is cyano; preferably, n is 1and R⁴ is cyano substituted in the para position relative to the NR³moiety.

Another special group of compounds contains those compounds of formula(I) or (I′) which are other than

-   (c)    N4-methyl-N2-(2-methylphenyl)-N4-phenyl-2,4,6-pyrimidinetriamine;-   (d) N4-methyl -N2-(2-methyl    phenyl)-N4-phenyl-6(phenylmethyl)-2,4-pyrimidine-diamine;-   (e) N4-(2-methylphenyl)-6-(phenylmethyl)-2,4-pyrimidinediamine; the    N-oxides, the pharmaceutically acceptable addition salts and the    stereochemically isomeric forms thereof.

An interesting group of compounds are those compounds of the presentinvention wherein the NR³(substituted phenyl or pyridyl) moiety is inthe 4- or 6-position of the pyrimidine ring.

Another interesting group are those compounds of the present inventionwherein each R⁴ independently is hydroxy, halo, C₁₋₆alkyloxy, cyano,aminocarbonyl, nitro, amino, trihalomethyl or trihalomethyloxy; R⁶ isphenyl or phenyl substituted with one, two or three, four or fivesubstituents each independently selected from halo, C₁₋₆alkyloxy,C₁₋₆alkylcarbonyl, cyano, nitro and trifluoromethyl; and aryl is phenylor phenyl substituted with one, two, three, four or five substituentseach independently selected from halo, C₁₋₆alkyloxy, cyano, nitro andtrifluoromethyl.

Suitably, Q is NR¹R² wherein R¹ is hydrogen, hydroxy, C₁₋₁₂alkyl,C₁₋₁₂alkyloxy, C₁₋₁₂alkylcarbonyl, C₁₋₁₂alkyloxycarbonyl, aryl, amino,mono- or di(C₁₋₁₂alkyl)amino, mono- or di(C₁₋₁₂alkyl)aminocarbonyl; andR² is hydroxy, C₁₋₁₂alkyl, C₁₋₁₂alkyloxy, C₁₋₁₂alkylcarbonyl,C₁₋₁₂alkyloxycarbonyl, aryl, amino, mono- or di(C₁₋₁₂alkyl)amino, mono-or di(C₁₋₁₂alkyl)aminocarbonyl; wherein each of the aforementionedC₁₋₁₂alkyl groups may optionally and each individually be substitutedwith one or two substituents each independently selected from hydroxy,C₁₋₆alkyloxy, hydroxyC₁₋₆alkyloxy, carboxyl, C₁₋₆alkyloxycarbonyl,cyano, amino, imino, aminocarbonyl, aminocarbonyl-amino, mono- ordi(C₁₋₆alkyl)amino, aryl and Het: or R¹ and R² taken together may formpyrrolidinyl, piperidinyl, morpholinyl, azido or mono- ordi(C₁₋₁₂alkyl)amino-C₁₋₄alkylidene.

Suitably, L is C₁₋₁₀alkyl substituted with one or two substituentsindependently selected from C₃₋₇cycloalkyl, indanyl, indolyl and phenyl,wherein said phenyl, indanyl and indolyl may be substituted with one,two, three, four or where possible five substituents each independentlyselected from halo, hydroxy, C₁₋₆alkyl, C₁₋₆alkyloxy, cyano,aminocarbonyl, C₁₋₆alkyloxycarbonyl, formyl, nitro, amino,trihalomethyl, trihalo-methyloxy and C₁₋₆alkylcarbonyl; or L is —X¹—R or—X²-Alk-R⁷ and when X¹ is NR³ then R⁶ is phenyl substituted with one,two, three, four or five substituents each independently selected fromC₁₋₆alkyloxycarbonyl, formyl, nitro and trihalomethyloxy.

Suitably, R⁴ or R^(4′) is nitro, trihalomethyloxy or C₁₋₆alkylsubstituted with cyano or aminocarbonyl.

Suitably, R⁶ is phenyl or phenyl substituted with one, two, three, fouror five substituents each independently selected from halo, hydroxy,C₁₋₆alkyl, C₁₋₆alkyloxy, C₁₋₆alkyloxycarbonyl, formyl, cyano,aminocarbonyl, nitro, amino, trihalomethyloxy and trihalomethyl.

Suitably, both Q and R⁵ are hydrogen.

Suitably, L is C₁₋₁₀alkyl substituted with one or two substituentsindependently selected from C₃₋₇cycloalkyl, indanyl, indolyl and phenyl,wherein said phenyl, indanyl and indolyl may be substituted with one,two, three, four or where possible five substituents each independentlyselected from halo, hydroxy, C₁₋₆alkyl, C₁₋₆alkyloxy, cyano,aminocarbonyl, C₁₋₆alkyloxycarbonyl, formyl, nitro, amino,trihalomethyl, trihalo-methyloxy and C₁₋₆alkylcarbonyl; or L is —X¹—R⁶or —X²-Alk-R⁷; and R⁵ is hydrogen.

Particular groups of compounds are those groups wherein one or more ofthe following conditions are met

-   -   (i) n is 0, 1, 2 or 3;    -   (ii) Q is hydrogen;    -   (iii) Q is NR¹R² wherein R¹and R² are each independently        selected from hydrogen, hydroxy, C₁₋₁₂alkyl. C₁₋₁₂alkyloxy,        C₁₋₁₂alkylcarbonyl, C₁₋₁₂alkyloxycarbonyl, cyano wherein the        aforementioned C₁₋₁₂alkyl groups may optionally and each        individually be substituted with one or two substituents each        independently selected from hydroxy, cyano, C₁₋₆alkyloxy,        hydroxyC₁₋₆alkyloxy, aryl and Het; or R¹ and R² taken together        may form mono- or di(C₁₋₁₂alkyl)aminoC₁₋₄alkylidene;    -   (iv) R³ is hydrogen or C₁₋₆alkyl:    -   (v) R⁴ is cyano, aminocarbonyl, amino, nitro, hydroxy, halo,        C₁₋₆alkyl or cyanoC₁₋₆alkyl;    -   (vi) R⁴ is cyano, aminocarbonyl, halo, C₁₋₆alkyl or        cyanoC₁₋₆alkyl;    -   (vii) R⁵ is hyrogen or methyl;    -   (viii) L is C₁₋₁₀alkyl substituted with phenyl substituted with        one or two halogens; or L is —X¹—R⁶ wherein R⁶ is phenyl        substituted with one, two or three substituents selected from        C₁₋₁₀alkyl, trifluoromethyl, trifluoromethoxy, cyano, and        halogen, and X¹ is —S—, —O— or —NR³—; or L is —X²-Alk-R⁷ wherein        R⁷ is phenyl substituted with one, two or three substituents        selected from C₁₋₆alkyl, cyano, and halogen and X² is NH.

Other particular compounds are those compounds of the present inventionwherein L contains phenyl, 2,6-disubstituted-phenyl,2,4,6-trisubstituted-phenyl or 2,3,4,5-tetra-substituted-phenyl;

-   -   especially, L contains phenyl, 2,4,6-trihalo-phenyl,        2,4,6-triC₁₋₄alkyl-phenyl, 2,3,4,5-tetrahalo-phenyl,        2,4-dihalo-6-C₁₋₄alkyl-phenyl, 2,6-dihalo-4-C₁₋₄alkyl-phenyl,        2,6-dihalo-4-cyano-phenyl, 2,6-dihalo-4-trifluoromethoxy-phenyl,        2,6-dihalo-4-trifluoromethyl-phenyl,        2,6-diC₁₋₄alkyl-4-halo-phenyl, 2,6-diC₁₋₄alkyl-4-cyano-phenyl,        2,6-dihalo-phenyl or 2,6-diC₁₋₄alkyl-phenyl;    -   more in particular, L contains phenyl, 2,4,6-trichloro-phenyl,        2,4,6-trimethyl-phenyl, 2,4-dibromo-3,5-dichloro-phenyl,        2,4-dibromo-6-fluoro-phenyl, 2,4-dichloro-6-methyl-phenyl,        2,6-dibromo-4-isopropyl-phenyl, 2,6-dibromo-4-methyl-phenyl,        2,6-dibromo-4-prop-1-yl-phenyl, 2,6-dichloro-4-cyano-phenyl,        2,6-dichloro-4-trifluoromethoxy-phenyl,        2,6-dichloro-4-trifluoromethyl-phenyl, 2,6-dichloro-phenyl,        2,6-dimethyl-4-(1,1-dimethylethyl)-phenyl, 2,6-dimethyl-phenyl,        2-bromo-4-fluoro-6-methyl-phenyl,        2-bromo-6-chloro-4-fluoro-phenyl, 4-bromo-2,6-dimethyl-phenyl,        4-chloro-2,6-dimethyl-phenyl, or 4-cyano-2,6-dimethyl-phenyl.

More particular compounds are the compounds of the present inventionwherein L is 2,6-dichlorobenzyl, or L is —X¹—R⁶ wherein X¹ is —NR³—, —S—or —O— and R⁶ is 2,4,6-tri-chlorophenyl, 2,4,6-trimethyl-phenyl,2,4-dibromo-3,5-dichloro-phenyl, 2,4-dibromo-6-fluoro-phenyl,2,4-dichloro-6-methyl-phenyl, 2,6-dibromo4-isopropyl-phenyl,2,6-dibromo-4-methyl-phenyl, 2,6-dibromo-4-prop-1-yl-phenyl,2,6-dichloro-4-cyano-phenyl, 2,6-dichloro-4-trifluoromethoxy-phenyl,2,6-dichloro-4-trifluoromethyl-phenyl, 2,6-dichloro-phenyl,2,6-dimethyl-4-(1,1-dimethylethyl)-phenyl, 2,6-dimethyl-phenyl,2-bromo-4-fluoro-6-methyl-phenyl, 2-bromo-6-chloro-4-fluoro-phenyl,4-bromo-2,6-dimethyl-phenyl, 4-chloro-2,6-dimethyl-phenyl,4-cyano-2,6-dimethyl-phenyl; or L is —X²-Alk-R⁷ wherein —X²-Alk- is—NH—CH₂— and R⁷ phenyl.

Still other particular compounds are those compounds of formula (I)where R³is hydrogen, A is CH, n is 1, and R⁴ is halo, methyl or cyanoand is positioned in the 4 position of the phenyl ring.

Preferred compounds are those compounds of the present invention whereinL is 2,6-dichlorobenzyl and the NR³(optionally substituted phenyl orpyridyl) moiety represents p-cyano-anilino and is in the 2 position ofthe pyrimidine ring.

Other preferred compounds are those compounds of the present inventionwherein Q is hydrogen. L is —X¹—R⁶ wherein X¹ is —NH— and R⁶ is2,4,6-trimethyl-phenyl or 4-cyano-2,6-dimethylphenyl, the NR³(optionallysubstituted phenyl or pyridyl) moiety represents p-cyano-anilino and isin the 2 position of the pyrimidine ring.

Still other preferred compounds are those compounds of the presentinvention wherein L is —X²-Alk-R⁷ wherein X² is —NH—, Alk is methyleneand R⁷ is phenyl, 2,6-dichloro-phenyl, 2,4,6-trimethyl-phenyl or4-cyano-2,6-dimethylphenyl.

More preferred are those compounds of formula (I′-1) wherein R^(4′) ishalo, cyano, aminocarbonyl or cyanoC₁₋₆alkyl; n is zero, A is CH, R³ ishydrogen; R⁵ is hydrogen or methyl; Q is hydrogen or NHR¹; and Lcontains phenyl, 2,4,6-trichloro-phenyl, 2,4,6-trimethyl-phenyl,2,4-dibromo-3,5-dichloro-phenyl, 2,4-dibromo-6-fluoro-phenyl,2,4-dichloro-6-methyl-phenyl, 2,6-dibromo-4-isopropyl-phenyl,2,6-dibromo-4-methyl-phenyl, 2,6-dibromo-4-prop-1-yl-phenyl,2,6-dichloro-4-cyano-phenyl, 2,6-dichloro-4-trifluoromethoxy-phenyl,2,6-dichloro-4-trifluoromethyl-phenyl, 2,6-dichloro-phenyl,2,6-dimethyl-4-(1,1-dimethylethyl)-phenyl, 2,6-dimethyl-phenyl,2-bromo-4-fluoro-6-methyl-phenyl, 2-bromo-6-chloro-4-fluoro-phenyl,4-bromo-2,6-dimethyl-phenyl, 4-chloro-2,6-dimethyl-phenyl, or4-cyano-2,6-dimethyl-phenyl.

Most preferred are

-   4-[[4-amino-6-[(2,6-dichlorophenyl)methyl]-2-pyrimidinyl]amino]benzonitrile;-   6-[(2,6-dichlorophenyl)methyl]-N2-(4-fluorophenyl)-2,4-pyrimidinediamine;-   4-[[4-[(2,4-dichlorophenyl)methyl]-6-[(4-hydroxybutyl)amino]-2-pyrimidinyl]amino]-benzonitrile;-   4-[[4-[(2,6-dichlorophenyl)methyl]-6-[(3-hydroxypropyl)amino]-2-pyrimidinyl]amino]-benzonitrile;-   N-[2-[(4-cyanophenyl)amino]-6-[(2,6-dichlorophenyl)methyl]-4-pyrimidinyl]-acetamide;-   N-[2-[(4-cyanophenyl)amino]-6-[(2,6-dichlorophenyl)methyl]-4-pyrimidinyl]-butanamide;-   4-[[2-amino-6-(2,6-dichlorophenoxy)-4-pyrimidinyl]amino]benzonitrile:-   4-[[4-[(2,6-dichlorophenyl)methyl]-6-[(2-hydroxy-2-phenylethyl)amino]-2-pyrimidinyl]amino]benzonitrile;-   4-[[4-[(2,6-dichlorophenyl)methyl]-6-[[3-(2-oxo-1-pyrrolidinyl)propyl]amino]-2-pyrimidinyl]amino]benzonitrile;-   4-[[4-[(2,6-dichlorophenyl)methyl]-6-[[2-(2-hydroxyethoxy)ethyl]amino]-2-pyrimidinyl]amino]benzontrile    monohydrochloride;-   4-[[4-[(2,6-dichlorophenyl)methyl]-6-[(2,3-dihydroxypropyl)amino]-2-pyrimidinyl]-amino]benzonitrile;-   4-[[4-[(2,6-dichlorophenyl)methyl]-6-(hydroxyamino)-2-pyrimidinyl]amino]-benzonitrile;-   4-[[4-[(2-cyanoethyl)amino]-6-[(2,6-dichlorophenyl)methyl]-2-pyrimidinyl]amino]-benzonitrile;-   4-[[4-[(2,6-dichlorophenyl)methyl]-6-[[2-(1-pyrrolidinyl)ethyl]amino]-2-pyrimidinyl]-amino]benzonitrile;-   4-[[4-amino-6-[(2,6-dichlorophenyl)methyl]-5-methyl-2-pyrimidinyl]amino]-benzonitrile;-   N2-(4-bromophenyl)-6-[(2,6-dichlorophenyl)methyl]-5-methyl-2,4-pyrimidinediamine;-   4-[[4-[(2,4,6-trimethylphenyl)amino]-2-pyrimidinyl]amino]benzonitrile;-   4-[[2-[(2,4,6-trimethylphenyl)amino]-4-pyrimidinyl]amino]benzonitrile;-   4-[[4-[(2,6-dimethylphenyl)amino]-2-pyrimidinyl]amino]benzonitrile;-   4-[[4-(2,4,6-trimethylphenoxy)-2-pyrimidinyl]amino]benzonitrile:-   4-[[4-[(2,6-dichlorophenyl)thio]-2-pyrimidinyl]amino]benzonitrile;-   4-[[4-[[2,6-dibromo-4-(1-methylethyl)phenyl]amino]-2-pyrimidinyl]amino]-benzonitrile;-   4-[[4-[[2,6-dichloro-4-(trifluoromethyl)phenyl]amino]-2-pyrimidinyl]amino]-benzonitrile;-   4-[[4-[(2,4-dichloro-6-methylphenyl)amino]-2-pyrimidinyl]amino]benzonitrile:-   4-[[2-[(cyanophenyl)amino]-4-pyrimidinyl]amino]-3,5-dimethylbenzonitrile;-   4-[[4-[(2,4-dibromo-6-fluorophenyl)amino]-2-pyrimidinyl]amino]benzonitrile;-   4-[[4-amino-6-[(2,6-dichlorophenyl)methyl]-5-methyl-2-pyrimidinyl]amino]-benzeneacetonitrile:-   4-[[4-[methyl](2,4,6-trimethylphenyl)amino]-2-pyrimidinyl]amino]benzonitrile;-   4-[[4-[(2,4,6-trichlorophenyl)amino]-2-pyrimidinyl]amino]benzonitrile;-   4-[[4-[(2,4,6-trimethylphenyl)thio]-2-pyrimidinyl]amino]benzonitrile;-   4-[[4-[(2,4.6-trimethylphenyl)amino-2-pyrimidiny]amino]benzonitrile;-   4-[[4-amino-6-[(2,4,6-trimethylphenyl)amino]-2-pyrimidinyl]amino]benzonitrile;-   4-[[2-amino-6-[(2,4,6-trimethylphenyl)amino]-4-pyrimidinyl]amino]benzonitrile;-   4-[[4-(2-bromo-4-chloro-6-methylphenoxy)-2-pyrimidinyl]amino]benzonitrile;-   4-[[4-[(4-chloro-2,6-dimethylphenyl)amino]-2-pyrimidinyl]amino]benzonitrile;-   3,5-dichloro-4-[[2-[(4-cyanophenyl)amino]-4-pyrimidinyl]amino]benzonitrile,-   4-[[4-[[2,6-dichloro-4-(trifluoromethoxy)phenyl]amino]-2-pyrimidinyl]amino]-benzonitrile;-   4-[[4-[(2,4-dibromo-3,6-dichlorophenyl)amino]-2-pyrimidinyl]amino]benzonitrile;-   4-[[4-[(2,6-dibromo-4-propylphenyl]amino]-2-pyrimidinyl]amino]benzonitrile;-   4-[[4-[(2,4 4,6-methylphenyl)amino]-2-pyrimidinyl]amino]benzamide;-   4-[[4-[(4-(1,1-dimethylethyl)-2,6-dimethylphenyl)amino]-2-pyrimidinyl]amino]-benzonitrile;-   4-[[2-[(4-cyanophenyl)amino]-4-pyrimidinyl]oxy]-3,5-dimethylbenzonitrile;-   4-[[4-[(4-chloro-2,6-dimethlphenyl)amino]-5-methyl-2-pyrimidinyl]amino]-benzonitrile;-   4-[[2-[(4-cyanophenyl)amino]-5-methyl-4-pyrimidinyl]amino-3,5-dimethyl-benzonitrile;-   4-[[4-[[4-(1,1-dimethylphenyl]amino]-5-methyl-2-pyrimidinyl]-amino]benzonitrile;-   4-[[4-[(4-bromo-2,6-dimethylphenyl)amino]-5-methyl-2-pyrimidinyl]amino]-benzonitrile;-   4-[[5-methyl-4-[(2,4,6-trimethylphenyl)thio]-2-pyrimidinylamino]benzonitrile;-   4-[[4-[(2,6-dibromo-4-propylphenyl)amino]-5-methyl-2-pyrimidinyl]amino]-benzonitrile;-   4-[[4-[(2,4,6-trimethylphenyl)amino]-2-pyrimidinyl]amino]benzamide,    N3-oxide;-   N2-(4-chlorophenyl)-4-(2,4,6-trimethylphenyl)-9,4-pyrimidinediamine;-   4-[[4-[[2,6-dibromo-4-(1-methylethyl)phenyl]amino]-5-methyl-2-pyrimidinyl]amino]-benzonitrile;-   4-[[2-[(4-cyanophenyl)amino]-5-methyl-4-pyrimidinyl]amino]-3,5-dimethyl    benzonitrile:-   4-[[4-[(phenylmethyl)amino]-2-pyrimidinyl]amino]benzonitrile;    the N-oxides, the pharmaceutically acceptable addition salts and the    stereochemically isomeric forms thereof.

The compounds of formula (I) can be prepared according to art-knownprocedures.

In particular, compounds of formula (I′) can generally be prepared byreacting an intermediate of formula (II-A) wherein W¹ is a suitableleaving group such as, for example, a halogen, with an amino derivativeof formula (III) optionally in a solvent such as, for example, water,2-propanol, diethylether, 1-methyl-2-pyrrolidinone and the like, andoptionally in the presence of an acid such as, for example, 1 Nhydrochloric acid in diethylether. It may be convenient to perform thereaction under a reaction-inert atmosphere such as, for example, oxygenfree argon or nitrogen.

In this and the following preparations, the reaction products may beisolated from the reaction medium and, if necessary, further purifiedaccording to methodologies generally known in the art such as, forexample, extraction, crystallization, distillation, trituration andchromatography.

Analogously to the reaction procedure described above, H—NR¹R² (VI) canalso be reacted with an intermediate of formula (II-B).

Suitable solvents for the above reaction include, for instance,2-propanol or 1,4-dioxane.

In case Q is NR¹R² and R² contains a hydroxy moiety, it may beconvenient to perform the above reaction with a protected form ofintermediate (VI) whereby the hydroxy moiety bears a suitable protectinggroup P being, for instance, a benzyl, and subsequently removing theprotective group according to art-known methodologies, such as, forexample, reacting with BBr₃ in dichloromethane under nitrogenatmosphere.

It is also possible to react H—X¹—R⁶ with an intermediate of formula(II-C) in a suitable solvent such as, for example, 1,4-dioxane, thusobtaining compounds of formula (I′) wherein L is —X¹—R⁶, said compoundsbeing represented by formula (I′-c).

Depending on the nature of X¹ a suitable base or acid may be used toimprove the reaction rate. For instance, in case X¹ is —O—, sodiumhydride may be used as suitable base; or in case X¹ is NR³, HCl may beused as a suitable acid.

The compounds of formula (I¹) may further be prepared by convertingcompounds of formula (I′) into each other according to art-known group,transformation reactions.

For instance, compounds of formula (I′) whereby Q is NR¹R² and R¹ and R²are taken together to form mono- or di(C₁₋₁₂alkyl)aminoC₁₋₄alkylidene,said compounds being represented by formula (I′-a), may be prepared byreacting a compound of formula (I′) wherein R¹ and R² are hydrogen, withan intermediate of formula (IV) or a functional derivative thereof.

Also, compounds of formula (I′) wherein Q is NR¹R² and R¹ and R² arehydrogen may further be reacted with an acyl halide or an alkylchloroformate in a reaction-inert solvent such as, for exampledichloromethane, in the presence of a suitable base, such as, forexample, pyridine, to form the corresponding amide, respectively,carbamate derivative.

Some of the compounds of formula (I′) and some of the intermediates inthe present invention may contain an asymmetric carbon atom. Purestereochemically isomeric forms of said compounds and said intermediatescan be obtained by the application of art-known procedures. For example,diastereoisomers can be separated by physical methods such as selectivecrystallization or chromatographic techniques, e.g. counter currentdistribution, liquid chromatography and the like methods. Enantiomerscan be obtained from racemic mixtures by first converting said racemicmixtures with suitable resolving agents such as, for example, chiralacids, to mixtures of diastereomeric salts or compounds; then physicallyseparating said mixtures of diastereomeric salts or compounds by, forexample, selective crystallization or chromatographic techniques, e.g.liquid chromatography and the like methods; and finally converting saidseparated diastereomeric salts or compounds into the correspondingenantiomers. Pure stereochemically isomeric forms may also be obtainedfrom the pure stereochemically isomeric forms of the appropriateintermediates and starting materials, provided that the interveningreactions occur stereospecifically.

An alternative manner of separating the enantiomeric forms of thecompounds of formula (I′) and intermediates involves liquidchromatography, in particular liquid chromatography using a chiralstationary phase.

The above specified reaction procedures for the preparation of compoundsof formula (I′) or subgroups thereof, can also be applied for thepreparation of compounds of formula (I).

Some of the intermediates and starting materials are known compounds andmay be commercially available or may be prepared according to art-knownprocedures.

Intermediates of formula (II-A) wherein Q is NR¹R², said intermediatesbeing represented by formula (II-A-1), can be prepared by reacting apyrimidine derivative of formula (V) wherein W² is a suitable leavinggroup such as, for example, a halogen, with HNR¹R² (VI) in a reactioninert solvent such as, for example, 1,4-dioxane, 2-propanol or the like.Different regio-specific isomers may be formed and can be separated fromone another using suitable separation techniques such as, for example,chromatography.

Intermediates of formula (II-B) can be prepared analogously to thepreparation of compounds of formula (I′) starting from intermediates(II-A) and (III).

A particular subgroup of the intermediates of formula (II-B) isrepresented by formula

Particular intermediates of formula (II′-B) are those wherein We is ahalogen, more in particular, a chloro atom.

Intermediates of formula (V) whereby Q is NR¹R² and the L is L′-CH₂ andis attached in the 2 position of the pyrimidine ring and W² is chloro,said intermediates being represented by formula (V-a), can be preparedby reacting an imidamide of formula (VII) with a propanedioic acid esterof formula (VIII) in a solvent such as, for example, ethanol, and in thepresence of, for instance, sodium, and subsequently reacting the thusformed intermediate of formula (IX) with a suitable reagent such as, forexample, phosphoryl chloride.

Intermediates of formula (V) whereby Q is NR¹R² and L is L′-CH₂ and isattached in the 4 or 6 position of the pyrimidine ring and W² is chloro,said intermediates being represented by formula (V-b), can be preparedby reacting an intermediate of formula (X) with urea or a functionalderivative thereof, in a solvent such as, for example, ethanol, and inthe presence of, for instance, sodium, and subsequently reacting thethus formed intermediate of formula (XI) with a suitable reagent suchas, for example, phosphoryl chloride.

Intermediates of formula (V) wherein Q is NR¹R² and L is L′-CH₂ and isattached anywhere on the pyrimidine ring, said intermediates beingrepresented by formula (V-c), can be prepared by reacting anintermediate of formula (XII-1), for Q is NR¹R² and formula (XII-2) forQ is hydrogen, wherein W² is a suitable leaving group such as, forexample, a halogen, with an intermediate of formula (XIII) wherein W³ isa suitable leaving group such as, for example, a halogen, according tothe procedure of a Grignard reaction.

Intermediates of formula (V) whereby Q is NR¹R² and L is —O—R⁶ or —NH—R⁶and is attached in the 4 or 6 position of the pyrimidine ring, saidintermediates being represented by formula (V-d), can be prepared byreacting an intermediate of formula (XIV) with an intermediate offormula (XII) wherein W² is a suitable leaving group such as, forexample, a halogen, in a reaction-inert solvent such as, for example,tetrahydrofuran or 1,4-dioxane, and in the presence of a suitable basesuch as, for example, potassium hydroxide or diisopropyl ethaneamine, orsodium hydride.

The intermediates of formula (V-a) to (V-d) can analogously be preparedfor the compounds of formula (I′) wherein Q is hydrogen. To this effect,there is one leaving group W² less on the pyrimidine ring of therespective starting material.

Compounds of formula (I′) and some of the intermediates may have one ormore stereogenic centers in their structure, present in a R or a Sconfiguration.

The compounds of formula (I′) as prepared in the hereinabove describedprocesses may be synthesized as a mixture of stereoisomeric forms, inparticular in the form of racemic mixtures of enantiomers which can beseparated from one another following art-known resolution procedures.The racemic compounds of formula (I) may be converted into thecorresponding diastereomeric salt forms by reaction with a suitablechiral acid. Said diastereomeric salt forms are subsequently separated,for example, by selective or fractional crystallization and theenantiomers are liberated therefrom by alkali. An alternative manner ofseparating the enantiomeric forms of the compounds of formula (I)involves liquid chromatography using a chiral stationary phase. Saidpure stereochemically isomeric forms may also be derived from thecorresponding pure stereochemically isomeric forms of the appropriatestarting materials, provided that the reaction occursstereospecifically. Preferably if a specific stereoisomer is desired,said compound will be synthesized by stereospecific methods ofpreparation. These methods will advantageously employ enantiomericallypure starting materials.

The compounds of the present invention and the intermediates of formula(II′-B) show antiretroviral properties, in particular against HumanImmunodeficiency Virus (HIV), which is the aetiological agent ofAcquired Immune Deficiency Syndrome (AIDS) in humans. The HIV viruspreferentially infects human T-4 cells and destroys them or changestheir normal function, particularly the coordination of the immunesystem. As a result, an infected patient has an ever decreasing numberof T-4 cells, which moreover behave abnormally. Hence, the immunologicaldefense system is unable to combat infections and neoplasms and the HTVinfected subject usually dies by opportunistic infections such aspneumonia, or by cancers. Other conditions associated with HIV infectioninclude thrombocytopaenia, Kaposi's sarcoma and infection of the centralnervous system characterized by progressive demyelination, resulting indementia and symptoms such as, progressive dysarthria, ataxia anddisorientation. HIV infection further has also been associated withperipheral neuropathy, progressive generalized lymphadenopathy (PGL) andAIDS-related complex (ARC).

The present compounds also show activity against HIV-1 strains that haveacquired resistance to art-known non-nucleoside reverse transcriptaseinhibitors. They also have little or no binding affinity to human α-1acid glycoprotein.

Due to their antiretroviral properties, particularly their anti-HIVproperties, especially their anti-HIV-1-activity, the compounds of thepresent invention are useful in the treatment of individuals infected byHIV and for the prophylaxis of these individuals. In general, thecompounds of the present invention may be useful in the treatment ofwarm-blooded animals infected with viruses whose existence is mediatedby, or depends upon, the enzyme reverse transcriptase. Conditions whichmay be prevented or treated with the compounds of the present invention,especially conditions associated with HIV and other pathogenicretroviruses, include AIDS, AIDS-related complex (ARC), progressivegeneralized lymphadenopathy (PGL), as well as chronic CNS diseasescaused by retroviruses, such as, for example HIV mediated dementia andmultiple sclerosis.

The compounds of the present invention or any subgroup thereof maytherefore be used as medicines against above-mentioned conditions. Saiduse as a medicine or method of treatment comprises the systemicadministration to HIV-infected subjects of an amount effective to combatthe conditions associated with HIV and other pathogenic retroviruses,especially HIV-1.

The compounds of the present invention or any subgroup thereof may beformulated into various pharmaceutical forms for administrationpurposes. As appropriate compositions there may be cited allcompositions usually employed for systemically administering drugs. Toprepare the pharmaceutical compositions of this invention, an effectiveamount of the particular compound, optionally in addition salt form, asthe active ingredient is combined in intimate admixture with apharmaceutically acceptable carrier, which carrier may take a widevariety of forms depending on the form of preparation desired foradministration. These pharmaceutical compositions are desirable inunitary dosage form suitable, particularly, for administration orally,rectally, percutaneously, or by parenteral injection. For example, inpreparing the compositions in oral dosage form, any of the usualpharmaceutical media may be employed such as, for example, water,glycols, oils, alcohols and the like in the case of oral liquidpreparations such as suspensions, syrups, elixirs and solutions; orsolid carriers such as starches, sugars, kaolin, lubricants, binders,disintegrating agents and the like in the case of powders, pills,capsules, and tablets. Because of their ease in administration, tabletsand capsules represent the most advantageous oral dosage unit forms, inwhich case solid pharmaceutical carriers are obviously employed. Forparenteral compositions, the carrier will usually comprise sterilewater, at least in large part, though other ingredients, for example, toaid solubility, may be included. Injectable solutions, for example, maybe prepared in which the carrier comprises saline solution, glucosesolution or a mixture of saline and glucose solution. Injectablesuspensions may also be prepared in which case appropriate liquidcarriers, suspending agents and the like may be employed. Also includedare solid form preparations which are intended to be converted, shortlybefore use, to liquid form preparations. In the compositions suitablefor percutaneous administration, the carrier optionally comprises apenetration enhancing agent and/or a suitable wetting agent, optionallycombined with suitable additives of any nature in minor proportions,which additives do not introduce a significant deleterious effect on theskin.

It is especially advantageous to formulate the aforementionedpharmaceutical compositions in dosage unit form for ease ofadministration and uniformity of dosage. Dosage unit form as used hereinrefers to physically discrete units suitable as unitary dosages, eachunit containing a predetermined quantity of active ingredient calculatedto produce the desired therapeutic effect in association with therequired pharmaceutical carrier. Examples of such dosage unit forms aretablets (including scored or coated tablets), capsules, pills, powderpackets, wafers, injectable solutions or suspensions and the like, andsegregated multiples thereof.

Those of skill in the treatment of HIV-infection could determine theeffective daily amount from the test results presented here. In generalit is contemplated that an effective daily amount would be from 0.01mg/kg to 50 mg/kg body weight, more preferably from 0.1 mg/kg to 10mg/kg body weight. It may be appropriate to administer the required doseas two, three, four or more sub-doses at appropriate intervalsthroughout the day. Said sub-doses may be formulated as unit dosageforms, for example, containing 1 to 1000 mg, and in particular 5 to 200mg of active ingredient per unit dosage form.

The exact dosage and frequency of administration depends on theparticular compound of formula (I) used, the particular condition beingtreated, the seventy of the condition being treated, the age, weight andgeneral physical condition of the particular patient as well as othermedication the individual may be taking, as is well known to thoseskilled in the art. Furthermore, it is evident that said effective dailyamount may be lowered or increased depending on the response of thetreated subject and/or depending on the evaluation of the physicianprescribing the compounds of the instant invention. The effective dailyamount ranges mentioned hereinabove are therefore only guidelines andare not intended to limit the scope or use of the invention to anyextent.

Also, the combination of an antiretroviral compound and a compound ofthe present invention can be used as a medicine. Thus, the presentinvention also relates to a product containing (a) a compound of thepresent invention, and (b) another antiretroviral compound, as acombined preparation for simultaneous, separate or sequential use inanti-HIV treatment. The different drugs may be combined in a singlepreparation together with pharmaceutically acceptable carriers. Saidother antiretroviral compounds may be known antiretroviral compoundssuch as nucleoside reverse transcriptase inhibitors, e.g. zidovudine(3′-azido-3′-deoxythymidine, AZT), didanosine (dideoxy inosine; ddI),zalcitabine (dideoxycytidine, ddC) or lamivudine(3′-thia-2′-3′-dideoxycytidine, 3TC) and the like; non-nucleosidereverse transcriptase inhibitors such as suramine, foscarnet-sodium(trisodium phosphono formate), nevirapine(11-cyclopropyl-5,11-dihydro-4-methyl-6H-dipyrido[3,2-b: 2′,3′-e][1,4]diazepin-6-one), sustiva (efavirenz), tacrine(tetrahydroaminoacridine) and the like; compounds of the TIBO(tetrahydro-imidazo[4,5,1-jk](1,4]-benzodiazepine-2(1H)-one andthione)-type e.g.(S)-8-chloro-4,5,6,7-tetrahydro-5-methyl-6-(3-methyl-2-butenyl)imidazo-[4,5,1-jk][1,4]benzodiazepine-2(1H)-thione; compounds of theα-APA (α-anilino phenyl acetamide) type e.g.α-[(2-nitro-phenyl)amino]-2,6-dichloro-benzene-acetamide and the like:TAT-inhibitors, e.g. RO-5-3335 and the like; protease inhibitors e.g.indinavir, ritanovir, saquinovir and the like; NMDA receptor inhibitorse.g. pentamidine; α-glycosidase inhibitor e.g. castanospermine and thelike; Rnase H inhibitor e.g. dextran (dextran sulfate) and the like: orimmunomodulating agents, e.g. levamisole, thymopentin and the like.

The following examples are intended to illustrate the present invention.

Experimental Part

A. INTERMEDIATE COMPOUNDS EXAMPLE A1

a) A solution of 2,6-dichlorobenzylchloride (0.102 mol) in1,1-diethylether (10 ml) was added dropwise to magnesium (0.102 mol) in1,1-diethylether (60 ml). The reaction was initiated by adding 2 dropsof 1,2-dibromoethane. After most of magnesium disappeared,2,4,6-trichloropyrimidine (0.051 mol) in 1,1-diethylether (30 ml) wasadded. The mixture was stirred overnight at room temperature. Thesolvent was evaporated and the residue was purified by flash columnchromatography over silica gel (eluent: CH₂Cl₂/hexane 1/2). The desiredfractions were collected and the solvent was evaporated, yielding 3.3 gof (21%) 2,4-dichloro-6-[(2,6-dichloro-phenyl)methyl]pyrimidine (interm.1; m.p.: 106-107 ° C.).

b) Intermediate (1) (0.0081 mol) in 2-propanol (100 ml) was heated untilcomplete dissolution. The solution was then transferred into a pressuretube and NH₃ gas was bubbled into it for 20 minutes. Then the mixturewas heated to 80 ° C. for 16 hours. The solvent was evaporated, yieldinga residue of two compounds:2-chloro-6-[(2,6-di-chloro-phenyl)methyl]-4-pyrimidinamine (interm. 2)and 4-chloro-6-[(2,6-dichloro-phenyl)methyl]-2-pyrimidinamine (interm.3).

EXAMPLE A2

a) Urea (0.03 mol) was added to a mixture of (±)-ethyl2,6-dichloro-phenyl-α-methyl-β-oxobutanoate (0.02 mol) in NaOC₂H₅ inethanol, (1M; 0.040 mol; 40 ml). The reaction mixture was stirred andrefluxed overnight. The solvent was evaporated, water was added and themixture was neutralized with 0.3 N HOAc. The precipitate was filteredoff and was further triturated with ether and then H₂O, then filteredoff and dried, yielding 2.2 g (39%) of6-[(2,6-dichloro-phenyl)methyl]-5-methyl-2,4(1H,3H)-pyrimidinedione(interm. 4).

b) A mixture of intermediate (4) (0.0095 mol) in phosphoryl chloride (50ml) was stirred and refluxed overnight. Excess of phosphoryl chloridewas then evaporated. Ice-water was added to the residue. A whiteprecipitate was formed, filtered off and dried. The residue was purifiedby flash column chromatography over silica gel (eluent: CH₂Cl₂). Thedesired fractions were collected and the solvent was evaporated,yielding 2.06 g (67%) of2,4-dichloro-6-[(2,6-dichloro-phenyl)methyl]-5-methyl-pyrimidine(interm. 5).

c) 4-chloro-6-[(2,6-dichloro-phenyl)methyl]-5-methyl-2-pyrimidinamine(interm. 6) and2-chloro-6-[(2,6-dichloro-phenyl)methyl]-5-methyl-4-pyrimidinamine(interm. 7) were prepared from intermediate 5 following the proceduresas described in example A1b.

EXAMPLE A3

a) To the stirred solution of 2,6-dichlorobenzeneethanimidamide HCl(1:1), (0.0042 mol) in ethanol (20 ml), a solution of sodium (0.013 mol)in ethanol (10 ml) was added dropwise first and then propanedioic acid,diethyl ester (0.0109 mol) was added. The reaction mixture was stirredand refluxed for 4 hours and then stirred at room temperature overnightAfter adding another equivalent of propanedioic acid, diethyl ester(stirring and refluxing it overnight), the solvent was evaporated andthe residue was dissolved in water and acidified with 1 N HCl. The solidwas filtered off, washed with water and dried, yielding 0.87 g (76.4%)of 2-[(2,6-dichloro-phenyl)methyl]-4,6-pyrimidinediol (interm. 8).

b) 6-chloro-2-[(2,6-dichloro-phenyl)methyl]-4-pyrimidinamine (interm. 9)was prepared starting from intermediate 8 according to the proceduresdescribed in example A.1.b, A2.b & A2.c.

EXAMPLE A4

4-Amino-1-butanol (1.57 ml) was added to a solution of intermediate (1)(0.008 mol) in 1,4-dioxane (20 ml) under Argon. The reaction mixture wasstirred for 2 hours at room temperature. The solvent was evaporated. Theresidue was purified by flash column chromatography over silica gel(eluent gradient: CH₂Cl₂/CH₃OH: from 100/0 to 98/2). The pure fractionswere collected and the solvent was evaporated, yielding 2.05 g of amixture of4-[[2-chloro-6-[(2,6-dichloro-phenyl)methyl]-4-pyrimidinyl]-amino]-1-butanol(interm. 10) and4-[[4-chloro-6-[(2,6-dichloro-phenyl)methyl]-2-pyrimidinyl]amino]-1-butanol(interm. 11).

EXAMPLE A5

a) Potassium hydroxide/ethanol (10%; 0.035 mol) was added to a solutionof 2,6-dichlorophenol (0.035 mol) in tetrahydrofuran (100 ml). Themixture was stirred and 2,4,6-trichloropyrimidine (0.044 mol) was added.The mixture was stirred overnight at 60° C. The reaction was quenchedwith NaOH 1N solution. The aqueous layers were extracted with EtOAcseveral times and then the organic layers were combined and washed withNaOH 3N and saturated NaCl, dried and concentrated. The residue wasrecrystallized from CH₂Cl₂/hexane. The precipitate was filtered off anddried, yielding 5.98 g 2,4-dichloro-6-(2,6-dichlorophenoxy)pyrimidine(55%) (interm. 12).

b) Reaction under Argon atmosphere. 2,4,6-trimethylaniline (0.0678 mol)was added to 2,4-dichloropyrimidine (0.0664 mol) in 1,4-dioxane (100ml). N,N-di(1-methylethyl)-ethaneamine (0.0830mol) was added. Thereaction mixture was stirred and refluxed for 4days and the solvent wasevaporated. The residue was dissolved in CH₂Cl₂, washed with a saturatedNaHCO₃ solution, then dried (Na₂SO₄), filtered and the solvent wasevaporated to give 17.1 g solid residue. This solid was dissolved inCH₂Cl₂:hexane (1:1; 150 ml), and the resulting solution was concentratedto 100 ml, then filtered. The residue was purified by columnchromatography on KP-Sil (eluent: CH₂Cl₂). The desired fractions werecollected and the solvent was evaporated. The less polar fraction wasstirred in CH₂Cl₂ for 3 hours and filtered, yielding 0.44 g4-chloro-N-(2,4,6-tri-methylphenyl)-2-pyrimidinamine (intermediate 48).A second fraction was recrystallized from acetonitrile, filtered off anddried, yielding 2-chloro-1V-(2,4,6-trimethyl-phenyl)-4-pyrimidinamine(intermediate 49).

EXAMPLE A6

Pyridine (1 ml) was added to a mixture of4-[[4-amino-6-[(2,6-dichloro-phenyl)-methyl]-2-pyrimidinyl]amino]benzonitrile(0.00135 mol) in CH₂Cl₂ (19 ml). A solution of chloroethanoyl chloride(0.001375 mol) in CH₂Cl₂ (0.5 ml) was added dropwise on an ice bath. Themixture was stirred at room temperature for 2 hours. More chloroethanoylchloride (0.00625 mol) in CH₂Cl₂ (0.5 ml) was added. The mixture stoodin the refrigerator overnight. The solvent was evaporated. The residuewas treated with a saturated Na₂CO₃ solution and the mixture wasextracted with CH₂Cl₂. The separated organic layer was dried, filteredand concentrated. The residue was purified by flash columnchromatography over silica gel (eluent: CH₂Cl₂/CH₃OH/NH₄OH 99/1/0.1).The desired fractions were collected and the solvent was evaporated,yielding 0.22 g (36.5%) of2-chloro-N-[6-[(2,6-dichloro-phenyl)methyl]-2-[(4-cyano-phenyl)amino]-4-pyrimidinyl]acetamide(intern. 13).

EXAMPLE A7

A mixture of 4-[(4-chloro-2-pyrimidinyl)amino]benzonitrile (0.005 mol)and nitryl tetrafluoroborate (0.0025 mol) in acetonitrile (5 ml) wasstirred at room temperature for 4 h. The material was quenched withsaturated bicarbonate (50 ml) on cracked ice. The mixture was allowed toreach room temperature, and the yellow solid was filtered off. The solidwas adsorbed onto silica and purified by column chromatography (eluent:30%, 50%, 60%. 70% CH₂Cl₂ in hexanes). The solvent of the desiredfraction was evaporated and the residue was dried, yielding 0.89 g (64%)of 3-nitro-4-[(4-chloro-2-pyrimidinyl)amino]benzonitrile.(interm. 51)

EXAMPLE A8

A mixture of 2,6-dichloro-N-(2,4,6-trimethylphenyl)-4-pyrimidinamine(0.00376 mol) in a 2.0 M solution of NH₃ in 2-propanol (25 ml) and a 0.5M solution of NH₃ in dioxane (25 ml) was heated in a pressure sample at110-115 ° C for 24 hours. The solvent was evaporated, and the residuewas chromatographed on Biotage (eluent: 1:1 CH₂Cl₂:hexane). The desiredfractions were collected and the solvent was evaporated, yielding amixture of 0.523 g of2-chloro-N4-(2,4,6-trimethylphenyl)-4,6-pyrimidine-diamine (interm. 53)and 0.101 g of6-chloro-N4-(2,4,6-trimethylphenyl)-2,4-pyrimidinediamine. (interm. 50)

Tables 1 and 2 list intermediates which were prepared analogous to oneof the above examples. TABLE 1a

Int. No. Ex. No. R^(a) R^(b) R^(c) X R⁵ R physical data melting point 6A2c Cl H Cl CH₂ CH₃ —NH₂ — 15 A1b Cl H Cl CH₂ H —NH—CH₃ — 16 A1b Cl H ClO H —NH—CH₃ 152-155° C. 17 A1b Cl H Cl O H —NH₂ — 19 A4 Cl H Cl CH₂ H—NH—(CH₂)₃—OH — 20 A4 Cl H Cl CH₂ H —NH—(CH₂)₂—OH 111-113° C. 21 A4 Cl HCl CH₂ H —NH—CH₂—CH(OH)—C₆H₅ 133-134° C. 22 A4 Cl H Cl CH₂ H

— 23 A4 Cl H Cl CH₂ H —NH—(CH₂)₂—O—(CH₂)₂OH 99-107° C. 24 A4 Cl H Cl CH₂H —NH—(CH₂)₂-(4-OCH₃—C₆H₄) 138-140° C. 25 A4 Cl H Cl CH₂ H—NH—(CH₂)₂-(3-OCH₃—C₆H₄) 132-135° C. 26 A4 Cl H Cl CH₂ H—NH—CH₂—CH(OH)—CH₂OH 116-118° C. 27 A4 Cl H Cl CH₂ H —NH—CH₂—C₆H₅137-139° C. 28 A4 Cl H Cl CH₂ H —NH—(CH₂)₂-(2-thienyl) 113-114° C. 29 A4Cl H Cl CH₂ H —NH—(CH₂)₂-(2-pyridyl) 113.5-114° C. 31 A4 Cl H Cl CH₂ H—NH—(CH₂)₂CN 151-153° C. 48 A5b CH₃ CH₃ CH₃ NH H —H 142-143° C. 50 A8CH₃ CH₃ CH₃ NH H —NH₂

TABLE 1b

Int. Ex. physical data No. No. R^(a) R^(b) R^(c) X R⁵ R melting point 14A2b H CN H NH H H 211-212° C. 18 A5b CH₃ CH₃ CH₃ NH CH₃ H 30 A2b H CN HNH CH₃ H 51 A7 NO₂ CN H NH H H 142-144° C.

TABLE 2

Int. No. Ex. No. R^(a) R^(b) R^(c) X R⁵ R physical data 7 A2c Cl H ClCH₂ CH₃ —NH₂ 32 A1b Cl H Cl CH₂ H —NH—CH₃ — 33 A4 Cl H Cl CH₂ H—NH—(CH₂)₂-(1-pyrrolidinyl) 134-135° C. 34 A4 Cl H Cl CH₂ H—NH—(CH₂)₂-(2-pyridyl) 130-133° C. 35 A4 Cl H Cl CH₂ H—NH—(CH₂)₂-(2-thienyl) 98-99° C. 36 A4 Cl H Cl CH₂ H—NH—(CH₂)₂-(3-OCH₃—C₆H₄) 104-109° C. 37 A4 Cl H Cl CH₂ H—NH—(CH₂)₂-(4-OCH—C₆H₄) 149-150° C. 38 A4 Cl H Cl CH₂ H —NH—(CH₂)₂CN137-139° C. 39 A4 Cl H Cl CH₂ H —NH—(CH₂)₂—O—(CH₂)₂OH — 40 A4 Cl H ClCH₂ H —NH—(CH₂)₂OH 170-173° C. 41 A4 Cl H Cl CH₂ H —NH—(CH₂)₃—O—CH(CH₃)₂— 42 A4 Cl H Cl CH₂ H —NH—(CH₂)₃—OH — 43 A4 Cl H Cl CH₂ H —NH—CH₂—C₆H₅171-172° C. 45 A4 Cl H Cl CH₂ H —NH—CH₂—CH(OH)—CH₂OH >60° C. 46 A4 Cl HCl CH₂ H —NH—O—CH₂—C₆H₅ 137-141° C. 47 A4 Cl H Cl CH₂ H

55-60° C. 49 A5b CH₃ CH₃ CH₃ NH H H 182-183° C. 52 A4 Cl H Cl CH₂ H—NH—CH₂—CH(OH)—C₆H₅ 75-83° C. 53 A1b CH₃ CH₃ CH₃ NH H —NH₂ 54 A5b CH₃CH₃ CH₃ NH CH₃ H 55 A5a Cl Cl Cl —O— H H 159-161° C.

B. COMPOUNDS OF FORMULA (I′) EXAMPLE B1

A mixture of intermediate (42) and intermediate (19) (0.004 mol) and4-amino-benzonitrile (0.0084 mol) were combined in a sealed tube andheated for 16 hours at 160° C. under Argon. The reaction mixture wasallowed to cool to room temperature and dissolved in CH₂Cl₂/CH₃OH 90/10(20 ml) and 5 g of silica gel was added. After evaporating the solvent,the residue was purified by flash column chromatography over silica gel(eluent gradient: CH₂Cl₂/CH₃OH: from 100/0 to 97/3). The desiredfraction was collected and the solvent was evaporated, yielding 0.31 g(18.1%) of4-[[4-[(2,6-di-chloro-phenyl)methyl]-6-[(3-hydroxypropyl)amino]-2-pyrimidinyl]amino]benzonitrile(compound 3).

EXAMPLE B2

Intermediates (47) and (22) (0.00399 mol) and 4-aminobenzonitrile(0.0012 mol) in 1-methyl-2-pyrrolidinone (3 ml) was stirred for 16 hoursat 130 ° C. under Argon. Then, the reaction mixture was cooled to roomtemperature and quenched with H₂O (200 ml). A precipitate formed, whichwas stirred for 16 hours, and separated by filtration over Celite. Theresidue was dissolved in CH₃OH/CH₂Cl₂ (10%, 200 ml), dried over K₂CO₃,filtered, and evaporated. This resulting material was further purifiedby flash column chromatography over silica gel (gradient eluent:CH₂Cl₂/CH₃OH from 100/0 to 95/5). The desired fraction was collected andthe solvent was evaporated, yielding 0.43 g (21.7%) of4-[[6-[(2,6-dichloro-phenyl)methyl]-2-[[3-(2-oxo-1-pyrrolidinyl)propyl]-amino]-4-pyrimidinyl]amino]benzonitrile(comp. 39: 104-114° C.).

EXAMPLE B3

HCl/diethyl ether (1N: 2.77 ml) was stirred into a solution ofintermediate (33) (0.00277 mol) in 1-methyl-2-pyrrolidinone (4 ml) underN₂ atmosphere. The reaction mixture was heated for 5 minutes. Next,4-aminobenzonitrile (0.0061 mol) was added and the reaction was heatedat 100 ° C. for 16 hours. Then, the reaction mixture was cooled to roomtemperature and diluted with ethylacetate (10 ml). The organic layer waswashed with NaOH (1 N; 2×100 ml), H₂O (2×100 ml), brine (50 ml),respectively, dried, filtered and the filtrate was evaporated. The crudematerial was purified by flash chromatography (eluent: 2.5-7.5% of CH₃OHcontaining 10% NH₄OH in CH₂Cl₂). The desired fractions were collectedand the solvent was evaporated. The residue was dried, yielding 0.160 g(12.0%) of4-[[4-[(2,6-dichloro-phenyl)methyl]-6-[[2-(1-pyrrolidinyl)ethyl]amino]-2-pyrimidinyl]amino]benzonitrile(comp. 13: mp. 80-85° C.).

EXAMPLE B4

A slurry of intermediate (14) (0.005 mol) in CH₂Cl₂ (150 ml) was stirredrapidly and cooled to 0° C. under nitrogen. BBr₃ (0.015 mol) wasintroduced by syringe. The reaction mixture was stirred rapidly for twohours. The reaction mixture was recooled to 0° C. and quenched with NaOH(aq. 1 N, 25 ml). The biphasic partial quench mixture gives aprecipitate which was filtered off and dried, yielding 2.5 g (91%) of4-[[4-[(2,6-dichloro-phenyl)methyl]-6-(hydroxyamino)-2-pyrimidinyl]amino]-benzonitriledihydrobromide pentahydrate (comp. 15: mp. 240-244° C.).

EXAMPLE B5

1,1-Dimethoxy-N,N-dimethylmethanamine (0.152 mol) was added to4-([4-amino-6-[(2,6-dichlorophenyl)methyl]-2-pyrimidinyl]amino]benzonitrile(0.0008 mol). The mixture was stirred at room temperature for 2 days andthen concentrated. The crude product was purified by flashchromatography over silica gel (eluent: CH₂Cl₂/CH₃OH 99/1). The desiredfraction was collected and the solvent was evaporated. The resultingresidue was triturated with hexane, yielding 0.15 g (42%) ofN-[2-[(4-cyano-phenyl)amino]-6-[(2,6-dichlorophenyl)methyl]-4-pyrimidinyl]-N,N-dimethyl-methanimidamide(comp. 26; mp. 175-180° C.).

EXAMPLE B6

Piperidine (0.12 ml) was added to a mixture of intermediate (13)(0.00047 mol) in tetrahydrofuran (20 ml). The mixture was stirred atroom temperature for 4 hours. More piperidine (0.14 ml) was added. Themixture was stirred for another 2 hours. The solvent was evaporated. Theresidue was purified by flash column chromatography over silica gel(CH₂Cl₂/CH₃OH/NH₄OH 99/1/0.1). The desired fractions were collected andthe solvent was evaporated, yielding 0.05 g (21.5%) ofN-[6-[(2,6-di-chloro-phenyl)methyl]-2-[(4-cyano-phenyl)amino]-4-pyrimidinyl]-1-piperidine-acetamide(comp. 25: mp. 175-180° C).

EXAMPLE B7

Pyridine (0.014 mol) was added to a mixture of4-[[4-amino-6-((2,6-dichlorophenyl)-methyl]-2-pyrimidinyl]amino]benzonitrile(0.0013 mol) in CH₂Cl₂. A solution of octanoyl chloride (1.5 equiv) inCH₂Cl₂ (0.5 ml) was added dropwise. The mixture was stirred at roomtemperature for 2 hours. More octanoyl chloride (3.5 equiv) in CH₂Cl₂was added dropwise. The mixture was stirred. The solvent was thenevaporated. The residue was treated with a saturated aqueous NaHCO₃solution and the mixture was extracted with CH₂Cl₂. The separatedorganic layer was dried, filtered and the solvent was evaporated to givethe crude product. The residue was recrystallized from CHCl₃ and hexane,yielding 0.443 g (68.6%) ofN-[6-[(2,6-dichloro-phenyl)methyl]-2-[(4-cyano-phenyl)amino]-4-pyrimidinyl]octanamide(comp. 17; mp. 135-137° C.).

EXAMPLE B8

a) A mixture of intermediate 49 (0.082 mol) and 5.4 N HCl in 2-propanol(0.086 mol) in water (300 ml) was stirred and warmed to 40-45 ° C. over30 minutes. 4-Amino-benzonitrile (0.242 mol) was added at 40-45 ° C. Thereaction mixture was stirred and refluxed for 4.5 hours, then cooled toroom temperature. The mixture was alkalized by portionwise addition ofNaHCO₃. This mixture was extracted with ethylacetate. The organic layerwas separated, washed with brine, dried, filtered and the solvent wasevaporated. This fraction was stirred in ethanol p.a. (100 ml), filteredoff, washed with ethanol (50 ml), then dried, yielding 23.1 g (86%)4-[[4-[(2,4,6-trimethylphenyl)-amino]-2-pyrimidinyl]amino]benzonitrile(compound 52).

b) A mixture of 4-[(4-chloro-2-pyrimidinyl)amino]benzonitrile (0.021mol) and HCl in 2-propanol (0.0095 mol) in water (30 ml) was stirred forone hour at 45 ° C. 4-amino-3,5-dimethyl-benzonitrile (0.025 mol) wasadded and the reaction mixture was stirred and refluxed overnight. Themixture was cooled to room temperature, then neutralized with NaHCO₃.This mixture was extracted with ethylacetate. The separated organiclayer was washed with brine, dried, filtered and the solvent evaporated.The residue was crystallized from CH₃CN, filtered off and dried. Theresidue was stirred in boiling CH₂Cl₂ (20 ml), then filtered off anddried. The residue was crystallized from methyl isobutyl keton, filteredoff and dried, yielding 0.3 g of4-[[2-[(cyanophenyl)amino]-4-pyrimidinyl]amino]-3,5-dimethylbenzonitrile(compound 69).

EXAMPLE B9

a) 4-[(4-chloro-2-pyrimidinyl)amino]benzonitrile (0.003 mol),2,6-dibromo-4-methyl-benzenamine (0.006 mol) and 1 M HCl in diethylether (4.5 ml) in 1,4-dioxane (10 ml) were combined in a tube and heatedunder Ar until all diethyl ether had evaporated. The tube was sealed andheated at 170° C. for 2.5 days. Silica gel was added, and the solventwas evaporated. The residue was purified by flash column chromatographyover silica gel (eluent gradient: CH₂Cl₂:CH₃OH:NHOH 100:0:0 to99:0.9:0.1). The desired fractions were collected and the solvent wasevaporated. The residue was recrystallized from acetonitrile, filteredoff and dried, yielding 0.22 g (15.9%) of4-[[4-[(2,6-dibromo-4-methylphenyl)amino]-2-pyrimidinyl]amino]benzonitrile(compound 61).

b) 4-[[4-[(4-chloro-5-methyl-2-pyrimidinyl]amino]benzonitrile (0.01541mol), 4-amino-3,5-dimethyl-benzonitrile (0.00219 mol),1-methyl-2-pyrrolidinone (4 ml), 1,4-dioxane (15 ml) anddiisopropylethylamine (0.0154 mol) were combined in a flask under astream of argon and heated at 160-230° C. for 16 hours. CH₂Cl₂ and 1NNaOH were added, and the mixture was stirred 1 hour and filtered to givea brown solid (*). The CH₂Cl₂ filtrate was separated and was evaporatedand purified by flash column chromatography (eluent: 2% CH₃OH/CH₂Cl₂).The desired fractions were combined, evaporated and the residue wasstirred in CH₂Cl₂. The solid precipitate was filtered off, combined withthe brown solid (*) and recrystallized from CH₃CN. The precipitate wasfiltered off and dried, yielding 1.57 g (29%) of4-[[2-[(4-cyanophenyl)amino]-5-methyl-4-pyrimidinyl]amino]-3,5-dimethylbenzonitrile(compound 89).

c) 2-[(4-cyanophenyl)amino]-4-pyrimidinyl trifluoromethanesulfonate(0.0022 mol) and 2,6-dichloro-4-(trifluoromethyl)-benzenamine (0.0044mol) were combined in 1,4-dioxane (2.5 ml) and heated in a sealed tubeunder Ar at 170° C. for 40 hours. The reaction mixture was allowed tocool to room temperature. Silica gel was added, and the solvent wasevaporated. The residue was purified by flash column chromatography oversilica gel (eluent gradient: CH₂C₂:CH₃OH:NH₄OH 100:0:0 to 97:2.7:0.3).The desired fractions were collected and the solvent was evaporated. Theresidue was recrystallized from CH₃CN, filtered off and dried, yielding0.086 g (9.2%) of4-[14-[[2,6-dichloro-4-(trifluoromethyl)-phenyl]amino]-2-pyrimidinyl]amino]benzonitrile(compound 66).

EXAMPLE B10

To a suspension of NaH (0.006 mol) in 1,4-dioxane (30 ml),2,4,6-trimethyl-phenol (0.006 mol) was added. The mixture was stirredfor 15 minutes at room temperature, and a clear solution formed.4-[(4-chloro-2-pyrimidinyl)amino]benzonitrile (0.004 mol) was added, andthe reaction mixture was heated to reflux under Argon for 15 hours. Thereaction mixture was allowed to cool to room temperature, 0.5 ml ofwater was added, followed by 4 g of silica gel, and the solvent wasevaporated. The residue was purified by flash column chromatography oversilica gel (eluent gradient: CH₂Cl₂:CH₃OH 100:0:0 to 97:3). The purefractions were collected and the solvent was evaporated, yielding 1.18 g(89.4%) of4-[(4-(2,4,6-trimethylphenoxy)-2-pyrimidinyl]amino]benzonitrile(compound 58).

EXAMPLE B11

Compound (52) (0.0015 mol) was stirred in boiling ethanol (8 ml). 6 MHCl in 2-propanol (0.0015 mol) was added and the salt was allowed tocrystallize out overnight at room temperature. The precipitate wasfiltered off, washed with 2-propanol and dried, yielding 0.47 g (86%) of4-[[4-[(2,4,6-trimethyl-phenyl)amino]-2-pyrimidinyl]amino]benzonitrilehydrochloride (1:1) (compound 53).

EXAMPLE B12

A mixture of compound (52) (0.00303 mol) and NaBO₃.4H₂O (0.00911 mol) inCH₃OH (30 ml) and H₂O (10 ml) was stirred and refluxed for 4 days. Thereaction mixture was cooled. The precipitate was filtered off and theprecipitate (*) was purified by flash column chromatography over silicagel (eluent: CH₂Cl₂/CH₃OH gradient from 100/0 to 95/5). The desiredfractions were collected and the solvent was evaporated, yielding 0.586g (56%) of4-[[4-[(2,4,6-trimethylphenyl)amino]-2-pyrimidinyl]amino]benzamide(compound 100). The filtrate (*) was purified by reversed-phase HPLC(eluent gradient: ((0.5% ammoniumacetate in H₂O)/CH₃CN90/10)/CH₃OH/CH₃CN (0 minutes) 75/25/0, (44 minutes) 0/50/50, (57minutes) 0/0/100, (61.1-70 minutes) 75/25/0). Three desired fractiongroups were collected and their solvent was evaporated, yielding 0.18 gof 4-[[4-[(2,4,6-trimethylphenyl)amino]-2-pyrimidinyl]amino]benzamide.N3-oxide (compound 106) and 0.030 g of4-[[4-[(2,4,6-trimethylphenyl)amino]-2-pyrimidinyl]amino]benzamide,N1-oxide (compound 107).

Tables 3, 4, 5 and 6 list the compounds of formula (1) that wereprepared according to one of the above examples. TABLE 3

Co. Ex. physical data No. No. NR¹R² (melting point in ° C.) 1 B2—NH—(CH₂)₄—OH 161-163° C. 2 B2 —NH—(CH₂)₂—OH 207-210° C. 3 B2—NH—(CH₂)₃—OH 152-154° C. 4 B2 —NH—CH₂—CHOH—C₆H₅ 158-165° C. 5 B2

48-56° C. 6 B2 —NH—(CH₂)₂—O—(CH₂)₂—OH 162-175° C.; HCl (1:1) 7 B2—NH—(CH₂)₃—O—CH(CH₃)₂ 181-182° C.; HCl (1:1) 8 B2—NH—(CH₂)₂-(3-OCH₃—C₆H₄) 72-80° C. 9 B2 —NH—CH₂—CHOH—CH₂OH 189-192° C.10 B2 —NH—(CH₂)₂-(4-OCH₃—C₆H₄) 72-80° C. 11 B2 —NH—O—CH₂—C₆H₅ — 12 B2—NH—CH₂—C₆H₅ — 13 B3 —NH—(CH₂)₂-(1-pyrrolidinyl) 80-85° C. 14 B2—NH—(CH₂)₂-(2-thienyl) — 15 B4 —NH—OH 240-244° C. 16 B2—NH—(CH₂)₂-(2-pyridyl) 75-80° C. 17 B7 —NH—CO—C₇H₁₅ 135-137° C. 18 B7—NH—CO—C₁₁H₂₃ 130-135° C. 19 B2 —NH—(CH₂)₂—CN 255° C.: HCl (1:1) 20 B7—NH—CO—O—C₂H₅ >200° C. 21 B7 —NH—CO—CH₃ 128-130° C. 22 B7—NH—CO—C₃H₇ >200° C. 23 B1 —NH₂ 94-97° C. 24 B1 —NH—CH₃ 178-180° C. 25B6 —NH—CO—CH₂-(1-piperidinyl) 175-180° C. 26 B5 —N═CH—N(CH₃)₂ 175-180°C.

TABLE 4

Co. No. Ex. No. R′ R″ R⁵ physical data (melting point) 27 B1 4-Br—C₆H₄ HH — 28 B1 H 4-Br—C₆H₄ H — 29 B1 4-Cl—C₆H₄ H H — 30 B1 H 4-Cl—C₆H₄ H — 31B1 H (3-Br-6-pyridyl) H — 32 B1 (3-Br-6-pyridyl) H H — 33 B1 4-F—C₆H₄ HH 77-80° C. 34 B1 H 4-F—C₆H₄ H >200° C. 35 B1 4-CH₃—C₆H₄ H H 76-79° C.36 B1 H 4-CH₃—C₆H₄ H 183-186° C. 37 B1 C₆H₅ H H 85-90° C. 38 B1 H C₆H₅ H182-187° C. 39 B2

4-CN—C₆H₄ H 104-114° C. 40 B2 (CH₂)₂—OH 4-CN—C₆H₄ H 247-250° C.; HCl(1:1) 41 B1 CH₃ 4-CN—C₆H₄ H >200° C. 42 B1 (CH₂)₃—OH 4-CN—C₆H₄ H 91-105°C. 43 B2 (CH₂)₄—OH 4-CN—C₆H₄ H 161-163° C. 45 B1 H 4-CN—C₆H₄ H >200° C.46 B1 H 4-CN—C₆H₄ CH₃ >200° C. 47 B1 4-CN—C₆H₄ H CH₃ >200° C. 48 B1 H4-Br—C₆H₄ CH₃ >200° C. 49 B1 4-Br—C₆H₄ H CH₃ 168-170° C.

TABLE 5

Co. No. Ex. No. R′ R″ R′′′ R⁵ physical data 50 B1 NH₂ 4-CN—C₆H₄O-(2,6-diCl—C₆H₃) H >200° C. 51 B1 CH₂-(2,6-diCl—C₆H₃) H —NH-(4-CN—C₆H₄)H >200 90 B9a NH-(2-NO₂-4-CN—C₆H₃) 2,4,6-triCH₃—C₆H₂ H H 165-168° C. 91NH-(3-OH-4-CN—C₆H₃) 2,4,6-triCH₃—C₆H₂ H H 92 B12 NH-(2,6-diCl—C₆H₃)2,6-diCl—C₆H₃ H H 164-166° C. 93 B9a NH-(2,4,6-triCH₃—C₆H₂) 4-CN—C₆H₄ HH 267-268° C. 94 B1 NH-(4-CN—C₆H₄) 2,4,6-triCH₃—C₆H₂ NH₂ H 263-264° C.95 B1 NH₂ 2,4,6-triCH₃—C₆H₂ —NH-(4-CN—C₆H₄) H 233-234° C. 96 B8aNH-(4-Cl—C₆H₄) 2,4,6-triCH₃—C₆H₂ H H 97 B8a NH-(2,4-diF—C₆H₃)2,4,6-triCH₃—C₆H₂ H H 98 B8a

2,4,6-triCH₃—C₆H₂ H H 99 B9a NH-(2,4,6-triCH₃—C₆H₂) 4-CN—C₆H₄ H CH₃200-201° C. 100 B11

2,4,6-triCH₃—C₆H₂ H H 101 B8a

2,4,6-triCH₃—C₆H₂ H H 102 B8a

2,4,6-triCH₃—C₆H₂ H H 103 B1

H —CH₂-(2,6-diCl—C₆H₃) CH₃ >200° C. 104 NH-(4-CN—C₆H₄) C₆H₅—CH₂— H H 105NH-(2,4,6-triCH₃—C₆H₂) 2,4,6-triCH₃—C₆H₂ H H

TABLE 6

Co. Ex. physical data No. No. X R⁵ R^(6a) R^(6b) R^(6c) R^(6d) (saltform: melting point) 52 B8a NH H CH₃ H CH₃ CH₃ 217-218° C. 53 B11 NH HCH₃ H CH₃ CH₃ HCl (1:1) 54 B11 NH H CH₃ H CH₃ CH₃ HBr (1:1) 55 B11 NH HCH₃ H CH₃ CH₃ L-tartrate 56 B9a NH H CH₃ H Br CH₃ HCl (1:1); 214-217° C.57 B9a NH H CH₃ H H CH₃ HCl (1:1); >270° C. 58 B10 O H CH₃ H CH₃ CH₃220-222° C. 59 B10 S H Cl H H Cl 225-226° C. 60 B3 O H Cl H Cl Cl279-280° C. 61 B9a NH H Br H CH₃ Br 230-233° C. 62 B9a NH H Br HCH(CH₃)₂ Br 198-200° C. 63 B3 NH CH₃ CH₃ H CH₃ CH₃ 236-237° C. 64 B10 OH Cl H Cl CH₃ 266-267° C. 65 B9a NH H Cl H H Cl 253-255° C. 66 B9c NH HCl H CF₃ Cl 239-240° C. 67 B9c NH H Br H F Cl 244-245° C. 68 B9a NH H ClH Cl CH₃ 217° C. 69 B8b or B9a NH H CH₃ H CN CH₃ 225-230° C. 70 B9c NH HBr H Br F 210-214° C. 71 B9c N(CH₃) H CH₃ H CH₃ CH₃ 218-219° C. 72 B9cNH H Cl H Cl Cl trifluoroacetate (1:1); 225-230° C. 73 B10 S H CH₃ H CH₃CH₃ 204.5-208° C. 74 B10 O H Br H Cl CH₃ 246-249° C. 75 B9c NH H CH₃ HCl CH₃ 206-207° C. 76 B9a NH H Cl H CN Cl >180° C. 77 B9c NH H Cl H OCF₃Cl 185-190° C. 78 B9c NH H Br Cl Br Cl >265° C. 79 B9c NH H Br H C₃H₇ Br215-218° C. 80 B9a NH H CH₃ H C(CH₃)₃ CH₃ 203-205° C. 81 B10 O H CH₃ HCN CH₃ 279-280° C. 82 B9c NH CH₃ CH₃ H Cl CH₃ 235-237° C. 83 B9b NH CH₃CH₃ H CN CH₃ H₂O (1:1) trifluoroacetate (1:1); 274-275° C. 84 B9c NH CH₃CH₃ H C(CH₃)₃ CH₃ 231-232° C. 85 B9c NH CH₃ CH₃ H Br CH₃ 218-219° C. 86B9c S CH₃ CH₃ H CH₃ CH₃ 229-230° C. 87 B9a NH CH₃ Br H C₃H₇ Br 197-198°C. 88 B9a NH CH₃ Br H CH(CH₃)₂ Br 157-158° C. 89 B9b NH CH₃ CH₃ H CNCH₃ >300° C.

C. PHARMACOLOGICAL EXAMPLE EXAMPLE C.1

A rapid, sensitive and automated assay procedure was used for the invitro evaluation of anti-HIV agents. An HIV-1 transformed T4-cell line.MT4, which was previously shown (Koyanagi et al., Init. J. Cancer, 36,445-451, 1985) to be highly susceptible to and permissive for HIVinfection served as the target cell line. Inhibition of the HIV-inducedcytopathic effect was used as the end point. The viability of both HIV-and mock-infected cells was assessed spectrophotometrically via the insitu reduction of 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazoliumbromide (MTT). The 50% cytotoxic concentration (CC₅₀ in μM) was definedas the concentration of compound that reduced the absorbance of themock-infected control sample by 50%. The percent protection achieved bythe compound in HIV-infected cells was calculated by the followingformula:${\frac{\left( {OD}_{T} \right)_{HIV} - \left( {OD}_{C} \right)_{HIV}}{\left( {OD}_{C} \right)_{MOCK} - \left( {OD}_{C} \right)_{HIV}}\quad{expressed}\quad{in}\quad\%},$

whereby (OD_(T))_(HIV) is the optical density measured with a givenconcentration of the test compound in HIV-infected cells: (OD_(C))_(HIV)is the optical density measured for the control untreated HIV-infectedcells: (OD_(C))_(MOCK) is the optical density measured for the controluntreated mock-infected cells: all optical density values weredetermined at 540 nm. The dose achieving 50% protection according to theabove formula was defined as the 50% inhibitory concentration (IC₅₀ inμM). The ratio of CC₅₀ to IC₅₀ was defined as the selectivity index(SI). The compounds of formula (I) were shown to inhibit HIV-1effectively. Particular IC₅₀, CC₅₀ and SI values are listed in Table 7hereinbelow. Co. IC₅₀ CC₅₀ No. (μM) (μM) SI 1 0.027 49.7 1860 20.035 >100 >2890 3 0.016 37.4 2558 4 0.315 >100 >317 5 0.094 56.2 598 60.020 24.4 1192 7 0.975 >100 >102 8 8.147 >100 >12 9 0.037 58.6 1587 102.529 >100 >39 12 1.683 55.1 32 13 0.005 7.8 1557 14 2.183 89.0 40 150.003 9.0 2857 16 0.389 41.2 105 17 0.167 9.1. 54 18 2.1 59.9 29 190.006 53.6 8642 20 0.026 36.5 1413 21 0.017 50.6 2910 22 0.035 12.2 34623 0.001 47.9 59935 24 0.020 54.0 2667 25 0.079 >100 >1272 26 0.011 33.52990 27 0.017 >20 >1169 28 0.079 >20 >253 29 0.015 >20 >1324 300.088 >20 >228 31 0.024 86.8 3630 32 0.403 >100 >248 33 0.042 43.4 103834 0.319 57.8 181 35 0.103 42.3 409 36 0.323 >100 >309 37 0.443 33.4 7538 2.449 32.4 13 39 1.531 >100 >65 40 0.253 40.2 158 41 1.986 34.2 17 420.352 35.5 88 43 0.603 >100 >165 45 0.010 56.3 5688 46 45.2 >100 >2 470.004 >100 >27027 48 44.2 >100 >1 49 0.058 45.2 786 50 0.518 52.0 100 510.452 >100 >221 52 0.001 2.08 2314 53 0.0006 1.3 2111 56 0.0023 1.9 83957 0.0007 0.8 1153 58 0.0029 >100 >34482 59 0.0012 >100 >83333 600.29 >100 >350 61 0.0007 0.1 155 62 0.0032 8.7 2716 63 0.0017 0.3 198 640.12 >100 >840 65 0.18 0.2 1 66 0.0085 19.9 2347 67 0.0024 0.4 152 680.001 1.4 1367 69 0.0004 4.7 11632 70 0.0006 5.8 9641 71 0.0063 45.87275 72 0.0007 0.5 705 73 0.0036 >100 >27777 74 0.010 >100 >9523 750.0021 1.9 911 76 0.0033 5.2 1580 77 0.0030 9.6 3188 78 0.0028 0.4 14479 0.0031 4.8 1547 80 0.011 8.7 771 81 0.0011 >100 >90909 82 0.0026 0.4151 83 0.0008 0.4 541 84 0.012 9.3 753 85 0.002 0.4 208 860.010 >100 >9803 87 0.0031 2.2 711 88 0.0027 2.1 767 89 0.0007 0.4 61990 3.4 30.8 9 91 0.0025 4.9 1976 92 45.0 >90.0 >2 93 0.0035 48.1 1374394 0.0022 11.1 5064 95 0.0006 7.7 12783 96 0.0031 5.8 1885 97 0.032 13.2415 98 2.0 13.8 7 99 0.16 59.7 367 100 0.075 0.8 10 101 0.053 29.5 558102 0.0082 0.5 63 103 0.022 >100 4555 104 0.0034 18.6 5476 105 52.1<52.1 <1

D. COMPOSITION EXAMPLES

The following formulations exemplify typical pharmaceutical compositionssuitable for systemic administration to animal and human subjects inaccordance with the present invention.

“Active ingredient” (A.I.) as used throughout these examples relates toa compound of formula (I) or a pharmaceutically acceptable addition saltthereof.

EXAMPLE D.1 Film-Coated Tablets

Preparation of Tablet Core

A mixture of 100 g of the A.I., 570 g lactose and 200 g starch was mixedwell and thereafter humidified with a solution of 5 g sodium dodecylsulfate and 10 g polyvinyl-pyrrolidone in about 200 ml of water. The wetpowder mixture was sieved, dried and sieved again. Then there was added100 g microcrystalline cellulose and 15 g hydrogenated vegetable oil.The whole was mixed well and compressed into tablets, giving 10.000tablets, each comprising 10 mg of the active ingredient.

Coating

To a solution of 10 g methyl cellulose in 75 ml of denaturated ethanolthere was added a solution of 5 g of ethyl cellulose in 150 ml ofdichloromethane. Then there were added 75 ml of dichloromethane and 2.5ml 1,2,3-propanetriol. 10 g of polyethylene glycol was molten anddissolved in 75 ml of dichloromethane. The latter solution was added tothe former and then there were added 2.5 g of magnesium octadecanoate, 5g of polyvinylpyrrolidone and 30 ml of concentrated color suspension andthe whole was homogenated. The tablet cores were coated with the thusobtained mixture in a coating apparatus.

1.-16. (canceled)
 17. The combination of a compound of formula (I)

a N-oxide, a pharmaceutically acceptable addition salt or astereochemically isomeric form thereof, wherein A is CH, CR⁴ or N, n is0, 1, 2, 3 or 4; Q is hydrogen or —NR¹R²; R¹ and R² are eachindependently selected from hydrogen, hydroxy, C₁₋₁₂alkyl C₁₋₁₂alkyloxy,C₁₋₁₂alkylcarbonyl C₁₋₁₂alkyloxycarbonyl, aryl, amino, mono- ordi(C₁₋₁₂alkyl)amino, mono- or di(C₁₋₁₂alkyl)aminocarbonyl wherein eachof the aforementioned C₁₋₁₂alkyl groups may optionally and eachindividually be substituted with one or two substituents eachindependently selected from hydroxy, C₁₋₆alkyloxy, hydroxyC₁₋₆alkyloxy,carboxyl, C₁₋₆alkyloxycarbonyl, cyano, amino, imino, aminocarbonyl,aminocarbonylamino, mono- or di(C₁₋₆alkyl)amino, aryl and Het; or R¹ andR² taken together may form pyrrolidinyl, piperidinyl, morpholinyl, azidoor mono- or di(C₁₋₁₂alkyl)aminoC₁₋₄alkylidene, R³ is hydrogen, aryl,C₁₋₆alkylcarbonyl, C₁₋₆alkyl, C₁₋₆alkyloxycarbonyl, C₁₋₆alkylsubstituted with C₁₋₆alkyloxycarbonyl; and each R⁴ independently ishydroxy, halo, C₁₋₆alkyl C₁₋₆alkyloxy, cyano, aminocarbonyl, nitro,amino, trihalomethyl, trihalomethyloxy or C₁₋₆alkyl substituted withcyano or aminocarbonyl, R⁵ is hydrogen or C₁₋₄alkyl; L is C₁₁alkyl,C₃₋₁₀alkenyl, C₃₋₁₀alkynyl, C₃₋₇cycloalkyl, or C₁₋₁₀alkyl substitutedwith one or two substituents independently selected from C₃₋₇cycloalkyl,indanyl, indolyl and phenyl, wherein said phenyl, indanyl and indolylmay be substituted with one, two, three, four or where possible fivesubstituents each independently selected from halo, hydroxy, C₁₋₆alkyl,C₁₋₆alkyloxy, cyano, aminocarbonyl, C₁₋₆alkyloxycarbonyl, formyl, nitro,amino, trihalomethyl, trihalomethyloxy and C₁₋₆alkylcarbonyl, or L is—X¹—R⁶ or —X²-Alk-R⁷ wherein R⁶ and R⁷ each independently are phenyl orphenyl substituted with one, two, three, four or five substituents eachindependently selected from halo, hydroxy, C₁₋₆alkyl, C₁₋₆alkyloxy,C₁₋₆alkylcarbonyl, C₁₋₆alkyloxycarbonyl, formyl, cyano, aminocarbonyl,nitro, amino, trihalomethyloxy and trihalomethyl; and X¹ and X² are eachindependently —NR³—, —NH—NH—, —N═N—, —O—, —S—, —S(═O)— or —S(═O)₂—; Alkis C₁₋₄alkanediyl; aryl is phenyl or phenyl substituted with one, two,three, four or five substituents each independently selected from halo,C₁₋₆alkyl, C₁₋₆alkyloxy, cyano, nitro and trifluoromethyl; Het is analiphatic or aromatic heterocyclic radical; said aliphatic heterocyclicradical is selected from pyrrolidinyl, piperidinyl, homopiperidinyl,piperazinyl, morpholinyl, tetrahydrofuranyl and tetrahydrothienylwherein each of said aliphatic heterocyclic radical may optionally besubstituted with an oxo group; and said aromatic heterocyclic radical isselected from pyrrolyl, furanyl, thienyl, pyridyl, pyrimidinyl,pyrazinyl and pyridazinyl wherein each of said aromatic heterocyclicradical may optionally be substituted with hydroxy, and anotherantiretroviral compound.
 18. The combination of a compound of formula(I-1′)

a N-oxide, a pharmaceutically acceptable addition salt or astereochemically isomeric form thereof, wherein A is CH, CR⁴ or N; Q ishydrogen or —NR¹R²; R¹ and R² are each independently selected fromhydrogen, hydroxy, C₁₋₁₂alkyl, C₁₋₁₂alkyloxy, C₁₋₁₂alkylcarbonyl,C₁₋₁₂alkyloxycarbonyl, aryl, amino, mono- or di(C₁₋₁₂alkyl)amino, mono-or di(C₁₋₁₂alkyl)aminocarbonyl wherein each of the aforementionedC₁₋₁₂alkyl groups may optionally and each individually be substitutedwith one or two substituents each independently selected from hydroxy,C₁₋₆alkyloxy, hydroxyC₁₋₆alkyloxy, carboxyl, C₁₋₆alkyloxycarbonyl,cyano, amino, imino, aminocarbonyl, aminocarbonylamino, mono- ordi(C₁₋₆alkyl)amino, aryl and Het, or R¹ and R² taken together may formpyrrolidinyl, piperidinyl, morpholinyl, azido or mono- ordi(C₁₋₁₂alkyl)aminoC,₄alkylidene; R³ is hydrogen, aryl,C₁₋₆alkylcarbonyl, C₁₋₆alkyl C₁₋₆alkyloxycarbonyl, C₁₋₆alkyl substitutedwith C₁₋₆alkyloxycarbonyl; and each R⁴ independently is hydroxy, halo,C₁₋₆alkyl, C₁₋₆alkyloxy, cyano, aminocarbonyl, nitro, amino,trihalomethyl, trihalomethyloxy or C₁₋₆alkyl substituted with cyano oraminocarbonyl; R⁵ is hydrogen or C₁₋₄ alkyl; L is C₁₋₁₀alkyl substitutedwith one or two substituents independently selected from C₃₋₇cycloalkyl,indanyl, indolyl and phenyl, wherein said phenyl, indanyl and indolylmay be substituted with one, two, three, four or where possible fivesubstituents each independently selected from halo, hydroxy, C₁₋₆alkyl,C₁₋₆alkyloxy, cyano, aminocarbonyl, C₁₋₆alkyloxycarbonyl, formyl, nitro,amino, trihalomethyl, trihalomethyloxy and C₁₋₆alkylcarbonyl; or L is—X¹—R⁶ wherein X¹ is —NR³—, or —O— and R⁶ is 2,4,6-trichlorophenyl,2,4,6-trimethyl-phenyl, 2,4-dibromo-3,5-dichloro-phenyl,2,4-dibromo-6-fluoro-phenyl, 2,4-dichloro-6-methyl-phenyl,2,6-dibromo-4-isopropyl-phenyl, 2,6-dibromo-4-methylphenyl,2,6-dibromo-4-prop-1-yl-phenyl, 2,6-dichloro-4-cyano-phenyl,2,6-dichloro-4-trifluoromethoxy-phenyl,2,6-dichloro-4-trifluoromethyl-phenyl, 2,6-dichloro-phenyl,2,6-dimethyl-4-(1,1-dimethylethyl)-phenyl, 2,6-dimethyl-phenyl,2-bromo-4-fluoro-6-methyl-phenyl, 2-bromo-6-chloro-4-fluoro-phenyl4-bromo-2,6-dimethyl-phenyl, 4-chloro-2,6-dimethyl-phenyl,4-cyano-2,6-dimethyl-phenyl; or L is —X²-Alk-R⁷ wherein R⁷ is phenyl orphenyl substituted with one, two, three, four or five substituents eachindependently selected from halo, hydroxy, C₁₋₆alkyl, C₁₋₆alkyloxy,C₁₋₆alkylcarbonyl, C₁₋₆alkyloxycarbonyl, formyl, cyano, aminocarbonyl,nitro, amino, trihalomethyloxy and trihalomethyl; and X² is —NR³—,—NH—NH—, —N═N—, —O—, —S—, —S(═O)— or —S(═O)₂—; Alk is C₁₋₄alkanediyl;aryl is phenyl or phenyl substituted with one, two, three, four or fivesubstituents each independently selected from halo, C₁₋₆alkyl,C₁₋₆alkyloxy, cyano, nitro and trifluoromethyl; Het is an aliphatic oraromatic heterocyclic radical; said aliphatic heterocyclic radical isselected from pyrrolidinyl, piperidinyl, homopiperidinyl, piperazinyl,morpholinyl, tetrahydrofuranyl and tetrahydrothienyl wherein each ofsaid aliphatic heterocyclic radical may optionally be substituted withan oxo group; and said aromatic heterocyclic radical is selected frompyrrolyl, furanyl, thienyl, pyridyl, pyrimidinyl, pyrazinyl andpyridazinyl wherein each of said aromatic heterocyclic radical mayoptionally be substituted with hydroxy; and R^(4′) is cyano,aminocarbonyl, or C₁₋₆alkyl substituted with cyano or aminocarbonyl; n′is 0, 1, 2 or 3; with the proviso that 0 is other than anilino,2,4,6-trinitro-anilino, 3-methoxy-anilino, 4-methoxy-anilino,3,4-dimethoxy-anilino, 3-chloro-4-fluoro-anilino, 4-cyano-anilino,2-(C₁₋₆alkyl)-anilino, 4-(C₁₋₆alkyl)-anilino, 3-chloro-anilino,4-bromo-anilino, 4-nitro-anilino and 4-chloro-anilino, and anotherantiretroviral compound.
 19. (canceled)
 20. A product containing (a) acompound of formula (I)

a N-oxide, a pharmaceutically acceptable addition salt or astereochemically isomeric form thereof, wherein A is CH, CR⁴ or N; n is0, 1, 2, 3 or 4; Q is hydrogen or —NR¹R²; R¹ and R² are eachindependently selected from hydrogen, hydroxy, C₁₋₁₂alkyl,C₁₋₁₂alkyloxy, C₁₋₁₂alkylcarbonyl, C₁₋₁₂alkyloxycarbonyl, aryl, amino,mono- or di(C₁₋₁₂alkyl)amino, mono- or di(C₁₋₁₂alkyl)aminocarbonylwherein each of the aforementioned C₁₋₁₂alkyl groups may optionally andeach individually be substituted with one or two substituents eachindependently selected from hydroxy, C₁₋₆alkyloxy, hydroxyC₁₋₆alkyloxy,carboxyl, C₁₋₆alkyloxycarbonyl, cyano, amino, imino, aminocarbonyl,aminocarbonylamino, mono- or di(C₁₋₆alkyl)amino, aryl and Het; or R¹ andR² taken together may form pyrrolidinyl, piperidinyl, morpholinyl, azidoor mono- or di(C₁₋₁₂alkyl)aminoC₁₋₄ alkylidene. R³ is hydrogen, aryl,C₁₋₆alkylcarbonyl, C₁₋₆alkyl, C₁₋₆alkyloxycarbonyl, C₁₋₆alkylsubstituted with C₁₋₆alkyloxycarbonyl; and each R⁴ independently ishydroxy, halo, C₁₋₆alkyl, C₁₋₆alkyloxy, cyano, aminocarbonyl, nitro,amino, trihalomethyl, trihalomethyloxy or C₁₋₆alkyl substituted withcyano or aminocarbonyl; R⁵ is hydrogen or C₁₋₄alkyl; L is C₁₋₁₀alkyl,C₃₋₁₀alkenyl, C₃₋₁₀alkynyl, C₃₋₇cycloalkyl, or C₁₋₁₀alkyl substitutedwith one or two substituents independently selected from C₃₋₇cycloalkyl,indanyl, indolyl and phenyl, wherein said phenyl, indanyl and indolylmay be substituted with one, two, three, four or where possible fivesubstituents each independently selected from halo, hydroxy, C₁₋₆alkyl,C₁₋₆alkyloxy, cyano, aminocarbonyl, C₁₋₆alkyloxycarbonyl, formyl, nitro,amino, trihalomethyl, trihalomethyloxy and C₁₋₆alkylcarbonyl; or L is—X¹—R⁶ or —X-Alk-R⁷ wherein R⁶ and R⁷ each independently are phenyl orphenyl substituted with one, two, three, four or five substituents eachindependently selected from halo, hydroxy, C₁₋₆alkyl, C₁₋₆alkyloxy,C₁₋₆alkylcarbonyl, C₁₋₆alkyloxycarbonyl, formyl, cyano, aminocarbonyl,nitro, amino, trihalomethyloxy and trihalomethyl; and X¹ and X² are eachindependently —NR³—, —NH—NH—, —N═N—, —O—, —S—, —S(═O)— or —S(═O)₂—; Alkis C₁₋₄alkanediyl; aryl is phenyl or phenyl substituted with one, two,three, four or five substituents each independently selected from halo,C₁₋₆alkyl, C₁₋₆alkyloxy, cyano, nitro and trifluoromethyl; Het is analiphatic or aromatic heterocyclic radical; said aliphatic heterocyclicradical is selected from pyrrolidinyl, piperidinyl, homopiperidinyl,piperazinyl, morpholinyl, tetrahydrofuranyl and tetrahydrothienylwherein each of said aliphatic heterocyclic radical may optionally besubstituted with an oxo group; and said aromatic heterocyclic radical isselected from pyrrolyl, furanyl, thienyl, pyridyl, pyrimidinyl,pyrazinyl and pyridazinyl wherein each of said aromatic heterocyclicradical may optionally be substituted with hydroxy, and (b) anotherantiretroviral compound, as a combined preparation for simultaneous,separate or sequential use in anti-HIV treatment.
 21. A productcontaining (a) a compound of formula (I′-1)

a N-oxide, a pharmaceutically acceptable addition salt or astereochemically isomeric form thereof, wherein A is CH, CR⁴ or N; Q ishydrogen or —NR¹R²; R¹ and R² are each independently selected fromhydrogen, hydroxy, C₁₋₁₂alkyl, C₁₋₁₂alkyloxy, C₁₋₁₂alkylcarbonyl,C₁₋₁₂alkyloxycarbonyl, aryl, amino, mono- or di(C₁₋₁₂alkyl)amino, mono-or di(C₁₋₁₂alkyl)aminocarbonyl wherein each of the aforementionedC₁₋₁₂alkyl soups may optionally and each individually be substitutedwith one or two substituents each independently selected from hydroxy,C₁₋₆alkyloxy, hydroxyC₁₋₆alkyloxy, carboxyl, C₁₋₆alkyloxycarbonyl,cyano, amino, imino, aminocarbonyl, aminocarbonylamino, mono- ordi(C₁₋₆alkyl)amino, aryl and Het; or R¹ and R² taken together may formpyrrolidinyl, piperidinyl, morpholinyl, azido or mono- ordi(C₁₋₁₂alkyl)aminoC₁₋₄alkylidene; R³ is hydrogen, aryl,C₁₋₆alkylcarbonyl, C₁₋₆alkyl, C₁₋₆alkyloxycarbonyl, C₁₋₆alkylsubstituted with C₁₋₆alkyloxycarbonyl; and each R⁴ independently ishydroxy, halo, C₁₋₆alkyl, C₁₋₆alkyloxy, cyano, aminocarbonyl, nitro,amino, trihalomethyl, trihalomethyloxy or C₁₋₆alkyl substituted withcyano or aminocarbonyl; R⁵ is hydrogen or C₁₋₄alkyl, L is alkylsubstituted with one or two substituents independently selected fromC₃₋₇cycloalkyl, indanyl, indolyl and phenyl, wherein said phenyl,indanyl and indolyl may be substituted with one, two, three, four orwhere possible five substituents each independently selected from halo,hydroxy, C₁₋₆alkyl, C₁₋₆alkyloxy, cyano, aminocarbonyl,C₁₋₆alkyloxycarbonyl, formyl, nitro, amino, trihalomethyl,trihalomethyloxy and C₁₋₆alkylcarbonyl; or L is —X¹—R⁶ wherein X¹ is—NR³—, or —O— and R⁶ is 2,4,6-trichlorophenyl, 2,4,6-trimethyl-phenyl,2,4-dibromo-3,5-dichloro-phenyl, 2,4-dibromo-6-fluoro-phenyl,2,4-dichloro-6-methyl-phenyl, 2,6-dibromo-4-isopropyl-phenyl,2,6-dibromo-4-methylphenyl, 2,6-dibromo-4-prop-1-yl-phenyl,2,6-dichloro-4-cyano-phenyl, 2,6-dichloro-4-trifluoromethoxy-phenyl,2,6-dichloro-4-trifluoromethyl-phenyl, 2,6-dichloro-phenyl,2,6-dimethyl-4-(1,1-dimethylethyl)-phenyl, 2,6-dimethyl-phenyl,2-bromo-4-fluoro-6-methyl-phenyl, 2-bromo-6-chloro-4-fluoro-phenyl,4-bromo-2,6-dimethyl-phenyl, 4-chloro-2,6-dimethyl-phenyl,4-cyano-2,6-dimethyl-phenyl; or L is —X²-Alk-R⁷ wherein R⁷ is phenyl orphenyl substituted with one, two, three, four or five substituents eachindependently selected from halo, hydroxy, C₁₋₆alkyl, C₁₋₆alkyloxy,C₁₋₆alkylcarbonyl, C₁₋₆alkyloxycarbonyl, formyl, cyano, aminocarbonyl,nitro, amino, trihalomethyloxy and trihalomethyl; and X² is —NR³—,—NH—NH—, —N═N—, —O—, —S—, —S(═O)— or —S(═O)₂—; Alk is C₁₋₄alkanediyl,aryl is phenyl or phenyl substituted with one, two, three, four or fivesubstituents each independently selected from halo, C₁₋₆alkyl,C₁₋₆alkyloxy, cyano, nitro and trifluoromethyl; Het is an aliphatic oraromatic heterocyclic radical; said aliphatic heterocyclic radical isselected from pyrrolidinyl, piperidinyl, homopiperidinyl, piperazinyl,morpholinyl, tetrahydrofuranyl and tetrahydrothienyl wherein each ofsaid aliphatic heterocyclic radical may optionally be substituted withan oxo group; and said aromatic heterocyclic radical is selected frompyrrolyl, furanyl, thienyl, pyridyl, pyrimidinyl, pyrazinyl andpyridazinyl wherein each of said aromatic heterocyclic radical mayoptionally be substituted with hydroxy; and R^(4′) is cyano,aminocarbonyl, or C₁₋₆alkyl substituted with cyano or aminocarbonyl, n′is 0, 1, 2 or 3; with the proviso that Q is other than anilino,2,4,6-trinitro-anilino, 3-methoxy-anilino, 4-methoxy-anilino,3,4-dimethoxy-anilino, 3-chloro-4-fluoro-anilino, 4-cyano-anilino,2-(C₁₋₆alkyl)-anilino, 4-(C₁₋₆alkyl)-anilino, 3-chloro-anilino,4-bromo-anilino, 4-nitro-anilino and 4-chloro-anilino, and (b) anotherantiretroviral compound, as a combined preparation for simultaneous,separate or sequential use in anti-HIV treatment.
 22. A pharmaceuticalcomposition comprising a pharmaceutically acceptable carrier and asactive ingredients (a) a compound of formula (I)

a N-oxide, a pharmaceutically acceptable addition salt or astereochemically isomeric form thereof, wherein A is CH, CR⁴or N, n is0, 1, 2, 3 or 4; Q is hydrogen or —NR¹R²; R¹ and R² are eachindependently selected from hydrogen, hydroxy, C₁₋₁₂alkyl,C₁₋₁₂alkyloxy, C₁₋₁₂alkylcarbonv, C₁₋₁₂alkyloxycarbonyl, aryl, amino,mono- or di(C₁₋₂alkyl)amino, mono- or di(C₁₋₁₂alkyl)aminocarbonylwherein each of the aforementioned C₁₋₁₂alkyl groups may optionally andeach individually be substituted with one or two substituents eachindependently selected from hydroxy, C₁₋₆alkyloxy, hydroxyC₁₋₆alkyloxy,carboxyl, C₁₋₆alkyloxycarbonyl, cyano, amino, imino, aminocarbonyl,aminocarbonylamino, mono- or di(C₁₋₆alkyl)amino, aryl and Het; or R¹ andR² taken together may form Dyrrolidinyl, piperidinyl, morpholinyl, azidoor mono- or diC₁₋₁₂alkyl)aminoC₁₋₄alkylidene, R³ is hydrogen, aryl,C₁₋₆alkylcarbonyl, C₁₋₆alkyl, C₁₋₆alkyloxycarbonyl, C₁₋₆alkylsubstituted with C₁₋₆alkyloxycarbonyl, and each R⁴ independently ishydroxy, halo, C₁₋₆alkyl, C₁₋₆alkyloxy, cyano, aminocarbonyl, nitro,amino, trihalomethyl, trihalomethyloxy or C₁₋₆alkyl substituted withcyano or aminocarbonyl; R⁵ is hydrogen or C₁₋₄alkyl; L is C₁₋₁₀alkyl,C₁₋₁₀alkenyl, C₃₋₁₀alkynyl, C₃₋₇cycloalkyl, or C₁₋₁₀alkyl substitutedwith one or two substituents independently selected from C₃₋₇cycloalkyl,indanyl, indolyl and phenyl, wherein said phenyl, indanyl and indolylmay be substituted with one, two, three, four or where possible fivesubstituents each independently selected from halo, hydroxy, C₁₋₆alkylC₁₋₆alkyloxy, cyano, aminocarbonyl, C₁₋₆alkyloxycarbonyl, formyl, nitro,amino, trihalomethyl, trihalomethyloxy and C₁₋₆alkylcarbonyl, or L is—X¹—R⁶ or —X²-Alk-R⁷ wherein R⁶ and R⁷ each independently are phenyl orphenyl substituted with one, two, three, four or five substituents eachindependently selected from halo, hydroxy C₁₋₆alkyl, C₁₋₆alkyloxy,C₁₋₆alkylcarbonyl, C₁₋₆alkyloxycarbonyl, formyl, cyano, aminocarbonyl,nitro, amino, trihalomethyloxy and trihalomethyl; and X¹ and X² are eachindependently —NR³—, —NH—NH—, —N═N—, —O—, —S—, —S(═O)— or —S(═O)₂—; Alkis C₁₋₄alkanediyl; aryl is phenyl or phenyl substituted with one, two,three, four or five substituents each independently selected from halo,C₁₋₆alkyl, C₁₋₆alkyloxy, cyano, nitro and trifluoromethyl; Het is analiphatic or aromatic heterocyclic radical; said aliphatic heterocyclicradical is selected from pyrrolidinyl, piperidinyl, homopiperidinyl,piperazinyl, morpholinyl, tetrahydrofuranyl and tetrahydrothienylwherein each of said aliphatic heterocyclic radical may optionally besubstituted with an oxo group, and said aromatic heterocyclic radical isselected from pyrrolyl, furanyl, thienyl, pyridyl, pyrimidinyl,pyrazinyl and pyridazinyl wherein each of said aromatic heterocyclicradical may optionally be substituted with hydroxy, and (b) anotherantiretroviral compound.
 23. A pharmaceutical composition comprising apharmaceutically acceptable carrier and as active ingredients (a) acompound of formula (I′-1)

a N-oxide, a pharmaceutically acceptable addition salt or astereochemically isomeric form thereof, wherein A is CH, CR₄ or N; Q ishydrogen or —NR¹R²; R¹ and R² are each independently selected fromhydrogen, hydroxy, C₁₋₁₂alkyl, C₁₋₁₂alkyloxy, C₁₋₁₂alkylcarbonyl,C₁₋₁₂alkyloxycarbonyl, aryl, amino, mono- or di(C₁₋₁₂alkyl)amino, mono-or di(C₁₋₁₂alkyl)aminocarbonyl wherein each of the aforementionedC₁₋₁₂alkyl groups may optionally and each individually be substitutedwith one or two substituents each independently selected from hydroxy,C₁₋₆alkyloxy, hydroxyC₁₋₆alkyloxy, carboxyl, C₁₋₆alkyloxycarbonyl,cyano, amino, imino, aminocarbonyl, aminocarbonylamino, mono- ordi(C₁₋₆alkyl)amino, aryl and Het: or R¹ and R² taken together may formpyrrolidinyl, piperidinyl, morpholinyl, azido or mono- ordi(C₁₋₁₂alkyl)aminoC₁₋₄alkylidene; R³ is hydrogen, aryl,C₁₋₆alkylcarbonyl, C₁₋₆alkyl, C₁₋₆alkyloxycarbonyl, C₁₋₆alkylsubstituted with C₁₋₆alkyloxycarbonyl; and each R⁴ independently ishydroxy, halo, C₁₋₆alkyl, C₁₋₆alkyloxy, cyano, aminocarbonyl, nitro,amino, trihalomethyl, trihalomethyloxy or C₁₋₆alkyl substituted withcyano or aminocarbonyl; R⁵ is hydrogen or C₁₋₄alkyl, L is C₁₋₁₀alkylsubstituted with one or two substituents independently selected fromC₃₋₇cycloalkyl, indanyl, indolyl and phenyl, wherein said phenyl,indanyl and indolyl may be substituted with one, two, three, four orwhere possible five substituents each independently selected from halo,hydroxy, C₁₋₆alkyl, C₁₋₆alkyloxy, cyano, aminocarbonyl,C₁₋₆alkyloxycarbonyl, formyl, nitro, amino, trihalomethyl,trihalomethyloxy and C₁₋₆alkylcarbonyl, or L is —X¹—R⁶ wherein X¹ is—NR³—, or —O— and R⁶ is 2,4,6-trichlorophenyl, 2,4,6-trimethyl-phenyl,2,4-dibromo-3,5-dichloro-phenyl, 2,4-dibromo-6-fluoro-phenyl,2,4-dichloro-6-methyl-phenyl, 2,6-dibromo-4-isopropyl-phenyl,2,6-dibromo-4-methylphenyl, 2,6-dibromo-4-prop-1-yl-phenyl,2,6-dichloro-4-cyano-phenyl, 2,6-dichloro-4-trifluoromethoxy-phenyl,2,6-dichloro-4-trifluoromethyl-phenyl, 2,6-dichloro-phenyl,2,6-dimethyl-4-(1,1-dimethylethyl)-phenyl, 2,6-dimethyl-phenyl,2-bromo-4-fluoro-6-methyl-phenyl, 2-bromo-6-chloro-4-fluoro-phenyl,4-bromo-2,6-dimethyl-phenyl, 4-chloro-2,6-dimethyl-phenyl,4-cyano-2,6-dimethyl-phenyl, or L is —X²-Alk-R⁷ wherein R⁷ is phenyl orphenyl substituted with one, two, three, four or five substituents eachindependently selected from halo, hydroxy, C₁₋₆alkyl, C₁₋₆alkyloxy,C₁₋₆alkylcarbonyl, C₁₋₆alkyloxycarbonyl, formyl, cyano, aminocarbonyl,nitro, amino, trihalomethyloxy and trihalomethyl; and X² is —NR³—,—NH—NH—, —N═N—, —O—, —S—, —S(═O)— or —S(═O)₂—; Alk is C₁₋₄alkanediyl;aryl is phenyl or phenyl substituted with one, two, three, four or fivesubstituents each independently selected from halo, C₁₋₆alkyl,C₁₋₆alkyloxy, cyano, nitro and trifluoromethyl; Het is an aliphatic oraromatic heterocyclic radical; said aliphatic heterocyclic radical isselected from pyrrolidinyl, piperidinyl, homopiperidinyl, piperazinyl,morpholinyl, tetrahydrofuranyl and tetrahydrothienyl wherein each ofsaid aliphatic heterocyclic radical may optionally be substituted withan oxo group, and said aromatic heterocyclic radical is selected frompyrrolyl, furanyl, thienyl, pyridyl, pyrimidinyl, pyrazinyl andpyridazinyl wherein each of said aromatic heterocyclic radical mayoptionally be substituted with hydroxy, and R^(4′) is cyano,aminocarbonyl, or C₁₋₆alkyl substituted with cyano or aminocarbonyl; n′is 0, 1, 2 or 3; with the proviso that 0 is other than anilino,2,4,6-trinitro-anilino, 3-methoxy-anilino, 4-methoxy-anilino,3,4-dimethoxy-anilino, 3-chloro-4-fluoro-anilino, 4-cyano-anilino,2-(C₁₋₆alkyl)-anilino, 4-(C₁₋₆alkyl)-anilino, 3-chloro-anilino,4-bromo-anilino, 4-nitro-anilino and 4-chloro-anilino, and (b) anotherantiretroviral compound.
 24. (canceled)
 25. A method of treatingnon-nucleoside reverse transcriptase inhibitor resistant HIV infectionin a subject in need thereof comprising administering to the subject aneffective amount of the compound of the formula (I′-1)

a N-oxide, a pharmaceutically acceptable addition salt or astereochemically isomeric form thereof, wherein A is CH, CR⁴ or N; Q ishydrogen or —NR¹R²; R¹ and R² are each independently selected fromhydrogen, hydroxy, C₁₋₁₂alkyl, C₁₋₁₂alkyloxy, C₁₋₁₂alkylcarbonyl,C₁₋₁₂alkyloxycarbonyl, aryl, amino, mono- or di(C₁₋₁₂alkyl)amino, mono-or di(C₁₋₁₂alkyl)aminocarbonyl wherein each of the aforementionedC₁₋₁₂alkyl groups may optionally and each individually be substitutedwith one or two substituents each independently selected from hydroxy,C₁₋₆alkyloxy, hydroxyC₁₋₆alkyloxy, carboxyl, C₁₋₆alkyloxycarbonyl,cyano, amino, imino, aminocarbonyl, aminocarbonylamino, mono- ordi(C₁₋₆alkyl)amino, aryl and Het; or R¹ and R² taken together may formpyrrolidinyl, piperidinyl, morpholinyl, azido or mono- ordi(C₁₋₁₂alkyl)aminoC₁₋₄alkylidene; R³ is hydrogen, aryl,C₁₋₆alkylcarbonyl, C₁₋₆alkyl, C₁₋₆alkyloxycarbonyl, C₁₋₆alkylsubstituted with C₁₋₆alkyloxycarbonyl; and each R⁴ independently ishydroxy, halo, C₁₋₆alkyl, C₁₋₆alkyloxy, cyano, aminocarbonyl, nitro,amino, trihalomethyl, trihalomethyloxy or C₁₋₆alkyl substituted withcyano or aminocarbonyl; R⁵ is hydrogen or C₁₋₄alkyl; L is C₁₋₁₀alkylsubstituted with one or two substituents independently selected fromC₃₋₇cycloalkyl, indanyl, indolyl and phenyl, wherein said phenyl,indanyl and indolyl may be substituted with one, two, three, four orwhere possible five substituents each independently selected from halo,hydroxy, C₁₋₆alkyl, C₁₋₆alkyloxy, cyano, aminocarbonyl,C₁₋₆alkyloxycarbonyl, formyl, nitro, amino, trihalomethyl,trihalomethyloxy and C₁₋₆alkylcarbonyl; or L is —X¹—R⁶ wherein X¹ is—NR³—, or —O— and R⁶ is 2,4,6-trichlorophenyl, 2,4,6-trimethyl-phenyl,2,4-dibromo-3,5-dichloro-phenyl, 2,4-dibromo-6-fluoro-phenyl,2,4-dichloro-6-methyl-phenyl, 2,6-dibromo-4-isopropyl-phenyl,2,6-dibromo-4-methylphenyl, 2,6-dibromo-4-prop-1-yl-phenyl,2,6-dichloro-4-cyano-phenyl, 2,6-dichloro-4-trifluoromethoxy-phenyl,2,6-dichloro-4-trifluoromethyl-phenyl, 2,6-dichloro-phenyl,2,6-dimethyl-4-(1,1-dimethylethyl)-phenyl, 2,6-dimethyl-phenyl,2-bromo-4-fluoro-6-methyl-phenyl, 2-bromo-6-chloro-4-fluoro-phenyl,4-bromo-2,6-dimethyl-phenyl, 4-chloro-2,6-dimethyl-phenyl,4-cyano-2,6-dimethyl-phenyl; or L is —X²-Alk-R⁷ wherein R⁷ is phenyl orphenyl substituted with one, two, three, four or five substituents eachindependently selected from halo, hydroxy, C₁₋₆alkyl, C₁₋₆alkyloxy,C₁₋₆alkylcarbonyl, C₁₋₆alkyloxycarbonyl, formyl, cyano, aminocarbonyl,nitro, amino, trihalomethyloxy and trihalomethyl; and X² is —NR³—,—NH—NH—, —N═N—, —O—, —S—, —S(═O)— or —S(═O)₂—; Alk is C₁₋₄alkanediyl;aryl is phenyl or phenyl substituted with one, two, three, four or fivesubstituents each independently selected from halo, C₁₋₆alkyl,C₁₋₆alkyloxy, cyano, nitro and trifluoromethyl; Het is an aliphatic oraromatic heterocyclic radical; said aliphatic heterocyclic radical isselected from pyrrolidinyl, piperidinyl, homopiperidinyl, piperazinyl,morpholinyl, tetrahydrofuranyl and tetrahydrothienyl wherein each ofsaid aliphatic heterocyclic radical may optionally be substituted withan oxo group; and said aromatic heterocyclic radical is selected frompyrrolyl, furanyl, thienyl, pyridyl, pyrimidinyl, pyrazinyl andpyridazinyl wherein each of said aromatic heterocyclic radical mayoptionally be substituted with hydroxy; and R^(4′) is cyano,aminocarbonyl, or C₁₋₆alkyl substituted with cyano or aminocarbonyl; n′is 0, 1, 2 or 3; with the proviso that Q is other than anilino,2,4,6-trinitro-anilino, 3-methoxy-anilino, 4-methoxy-anilino,3,4-dimethoxy-anilino, 3-chloro-4-fluoro-anilino, 4-cyano-anilino,2-(C₁₋₆alkyl)-anilino, 4-(C₁₋₆alkyl)-anilino, 3-chloro-anilino,4-bromo-anilino, 4-nitro-anilino and 4-chloro-anilino.
 26. A method oftreating non-nucleoside reverse transcriptase inhibitor resistant HIV-1infection in a subject in need thereof comprising administering to thesubject an effective amount of the compound of the formula (I′-1)

a N-oxide, a pharmaceutically acceptable addition salt or astereochemically isomeric form thereof, wherein A is CH, CR⁴ or N; Q ishydrogen or —NR¹R²; R¹ and R² are each independently selected fromhydrogen, hydroxy, C₁₋₁₂alkyl, C₁₋₁₂alkyloxy, C₁₋₁₂alkylcarbonyl,C₁₋₁₂alkyloxycarbonyl, aryl, amino, mono- or di(C₁₋₁₂alkyl)amino, mono-or di(C₁₋₁₂alkyl)aminocarbonyl wherein each of the aforementionedC₁₋₁₂alkyl groups may optionally and each individually be substitutedwith one or two substituents each independently selected from hydroxy,C₁₋₆alkyloxy, hydroxyC₁₋₆alkyloxy, carboxyl, C₁₋₆alkyloxycarbonyl,cyano, amino, imino, aminocarbonyl, aminocarbonylamino, mono- ordi(C₁₋₆alkyl)amino, aryl and Het; or R¹ and R² taken together may formpyrrolidinyl, piperidinyl, morpholinyl, azido or mono- ordi(C₁₋₁₂alkyl)aminoC₁₋₄alkylidene; R³ is hydrogen, aryl,C₁₋₆alkylcarbonyl, C₁₋₆alkyl, C₁₋₆alkyloxycarbonyl, C₁₋₆alkylsubstituted with C₁₋₆alkyloxycarbonyl; and each R⁴ independently ishydroxy, halo, C₁₋₆alkyl, C₁₋₆alkyloxy, cyano, aminocarbonyl, nitro,amino, trihalomethyl, trihalomethyloxy or C₁₋₆alkyl substituted withcyano or aminocarbonyl; R⁵ is hydrogen or C₁₋₄alkyl; L is C₁₋₁₀alkylsubstituted with one or two substituents independently selected fromC₃₋₇cycloalkyl, indanyl, indolyl and phenyl, wherein said phenyl,indanyl and indolyl may be substituted with one, two, three, four orwhere possible five substituents each independently selected from halo,hydroxy, C₁₋₆alkyl, C₁₋₆alkyloxy, cyano, aminocarbonyl,C₁₋₆alkyloxycarbonyl, formyl, nitro, amino, trihalomethyl,trihalomethyloxy and C₁₋₆alkylcarbonyl; or L is —X¹—R⁶ wherein X¹ is—NR³—, or —O— and R⁶ is 2,4,6-trichlorophenyl, 2,4,6-trimethyl-phenyl,2,4-dibromo-3,5-dichloro-phenyl, 2,4-dibromo-6-fluoro-phenyl,2,4-dichloro-6-methyl-phenyl, 2,6-dibromo-4-isopropyl-phenyl,2,6-dibromo-4-methylphenyl, 2,6-dibromo-4-prop-1-yl-phenyl,2,6-dichloro-4-cyano-phenyl, 2,6-dichloro-4-trifluoromethoxy-phenyl,2,6-dichloro-4-trifluoromethyl-phenyl, 2,6-dichloro-phenyl,2,6-dimethyl-4-(1,1-dimethylethyl)-phenyl, 2,6-dimethyl-phenyl,2-bromo-4-fluoro-6-methyl-phenyl, 2-bromo-6-chloro-4-fluoro-phenyl,4-bromo-2,6-dimethyl-phenyl, 4-chloro-2,6-dimethyl-phenyl,4-cyano-2,6-dimethyl-phenyl; or L is —X²-Alk-R⁷ wherein R⁷ is phenyl orphenyl substituted with one, two, three, four or five substituents eachindependently selected from halo, hydroxy, C₁₋₆alkyl, C₁₋₆alkyloxy,C₁₋₆alkylcarbonyl, C₁₋₆alkyloxycarbonyl, formyl, cyano, aminocarbonyl,nitro, amino, trihalomethyloxy and trihalomethyl; and X² is —NR³—,—NH—NH—, —N═N—, —O—, —S—, —S(═O)— or —S(═O)₂—; Alk is C₁₋₄alkanediyl;aryl is phenyl or phenyl substituted with one, two, three, four or fivesubstituents each independently selected from halo, C₁₋₆alkyl,C₁₋₆alkyloxy, cyano, nitro and trifluoromethyl; Het is an aliphatic oraromatic heterocyclic radical; said aliphatic heterocyclic radical isselected from pyrrolidinyl, piperidinyl, homopiperidinyl, piperazinyl,morpholinyl, tetrahydrofuranyl and tetrahydrothienyl wherein each ofsaid aliphatic heterocyclic radical may optionally be substituted withan oxo group; and said aromatic heterocyclic radical is selected frompyrrolyl, furanyl, thienyl, pyridyl, pyrimidinyl, pyrazinyl andpyridazinyl wherein each of said aromatic heterocyclic radical mayoptionally be substituted with hydroxy; and R^(4′) is cyano,aminocarbonyl, or C₁₋₆alkyl substituted with cyano or aminocarbonyl; n′is 0, 1, 2 or 3; with the proviso that Q is other than anilino,2,4,6-trinitro-anilino, 3-methoxy-anilino, 4-methoxy-anilino,3,4-dimethoxy-anilino, 3-chloro-4-fluoro-anilino, 4-cyano-anilino,2-(C₁₋₆alkyl)-anilino, 4-(C₁₋₆alkyl)-anilino, 3-chloro-anilino,4-bromo-anilino, 4-nitro-anilino and 4-chloro-anilino.